CONTENTS

S
l.N Page No
Titles
o

Abbreviations used 12 - 13
1

Introduction
2 14 - 37

38 - 60
3 Review of Literature

Aim and Scope of the work

4 61 - 65

Systems and Methods

5 66 - 78

Results & Discussion

6 79 - 108

Summary and conclusions 109 - 113

7

References 114 - 141

8
 LIST OF FIGURES

Fig .1: Wire frame model of epidermal growth factor receptor

Fig: 2. Structure of Iressa

Fig: 3. Structure of Curcumin

Fig 4: Modified drug Iressa A

Fig : 5 : Modified drug Iressa B

Fig : 6. Modified drug iressa C

Fig: 7. Structure of curcumin

Fig.8: 3D structure of Curcumin

Fig 9.: 3D structure of standard drug Iressa

Fig 10: 3D structure of standard drug Iressa A

Fig 11:3D structure of standard drug Iressa B

Fig 12: 3D structure of standard drug Iressa C

Fig 13: Docking result of standard Iressa drug

Fig 14: Docking result of modified Iressa A drug

Fig 15: Docking result of modified drug Iressa B

Fig 16: Docking result of modified drug Iressa C

Fig 18: Docking result of natural Curcumin drug

Fig 19: Interaction energy of standard Iressa drug

Fig .20 :Interaction energy of modified drug Iressa A

Fig 21:Interaction energy of modified drug Iressa B

Fig. 22.Interaction Energy Graph of Modified Drug Iressa C

Fig 23. Interaction Energy Graph of Natural Drug Curcumin

LIST OF GRAPHS

Graph 1. Comparison of docking score and interaction energy values

Graph 2. Molecular weight comparison

Graph 3. Comparison of Hydrogen bond donors

Graph 4. Comparison of hydrogen bond acceptors

Graph 5. Comparison of Log P values (Partition coefficient)

 LIST OF TABLES

Table 1. Comparison of docking results and interaction energy values

Table 2. COMPARISON OF ADME toxic values

 ABBREVIATIONS USED

SCLC – Small cell lung cancer

NSCLC – Non small cell lung Cancer

MVP – Mitomycin vinblastin and Cis plastin

EC – ecoposide and Carboplatin

MIC – Mitomycin ifosfamide and cisplatin

EGFR – Epidermal growth factor receptor

BZLF1 – Barn H fragment Z left fram 1

EBV – Epstein bar Virus

DR - LUC CELL

GCL – Glutamate cystine ligate

GSTP1 – Glutathione S- transferase P1 S-1

TRAIL – Tumor neurosis factor related apoptosis inducing ligand

DNA – Deoxy ribonucleic acid

HL – Human leukemia

ER – Estrogen receptor

MMP – Matrix metallo proteinase

TIMP - Tissue inhibitor of metallo proteinase

NO – Nitric oxide

CYP – cytochrome P450

15d-PGJ2 - 15-deoxy-D12,14-prostaglandin J2

COX-2 - cyclooxygenase-2
GAPDH - glyceraldehyde phosphate dehydrogenase

IBD -inflammatory bowel disease

NF-κB - nuclear factor kappa B

PPAR - peroxisome proliferator-activated receptor

PGE2 - prostaglandin E2

RNA - ribonucleic acid

RT-PCR - reverse-transcription polymerase chain reaction

TNBS - trinitrobenzene sulphonic acid

 INTRODUCTION

CANCER is the name for diseases in which the body's cells become abnormal and

divide without control. Cancer cells may invade nearby tissues. And they may spread

through the bloodstream and lymphatic system to other parts of the body.

Cancer is a group of many related diseases that begin in cells, the body's basic

unit of life. Normally, cells grow and divide to produce more cells only when the body

needs them. Sometimes, however, cells become abnormal and keep dividing to form

more cells without control or order, creating a mass of excess tissue called a tumor.

Tumors can be malignant (cancerous) or benign (not cancerous).

The cells in malignant tumors can invade and damage nearby tissue and organs.

Cancer cells can also break away from a malignant tumor and travel through the

bloodstream or lymphatic system to form new tumors in other parts of the body.

Most cancers are named for the organ or type of cell in which they begin. For

example, cancer that begins in the lung is lung cancer, and cancer that begins in cells in

the skin known as melanocytes is called melanoma.

When cancer cells spread (metastasize) from their original location to another part

of the body, the new tumor has the same kind of abnormal cells and the same name as the

primary tumor. For example, if lung cancer spreads to the brain, the cancer cells in the

brain are actually lung cancer cells. The disease is called metastatic lung cancer (it is not

brain cancer).

Use the links below to find information on specific types of cancer, including

treatment options, expertise at The James, clinical trials, and frequently asked questions.
Formation of Cancer

The lining of the airways and windpipe is made up of rectangular-shaped surface

cells (columnar epithelium) and glands that produce mucus and other fluids. In healthy

lungs, these cells divide in a controlled and orderly way. But when a cell becomes

cancerous, it can continue to reproduce even when new cells aren't needed.

Although it may take years for lung cancer to develop, changes in lung tissue can

begin almost immediately after your lungs are exposed to the cancer-causing substances

(carcinogens) in cigarette smoke. With repeated exposure, normal cells are increasingly

damaged, and eventually some may become cancerous. Because of the way lung cancer

cells behave and because these cells have easy access to a large number of blood and

lymph vessels, cancerous cells may spread to other parts of your body before you ever

experience symptoms.

Types of Cancer

Common Cancers

Bone Cancer, Breast Cancer ,Endocrine Cancer ,Gastrointestinal Cancer,

Gynecologic Cancer, Head and Neck Cancer ,Leukemia , Lung Cancer, Lymphoma ,
Prostate Cancer ,Skin Cancer ,Soft Tissue Sarcoma
Lungs

When you breathe in, air passes from your nose or mouth through the windpipe

(trachea), which divides into two tubes (airways), one going to each lung. These are

known as the right and left bronchus and they divide to form smaller tubes called

bronchioles, which carry air through the lungs. At the end of the bronchioles are millions
of tiny air sacs called alveoli. In the alveoli, oxygen is absorbed from the air and passes

into the bloodstream to be circulated around the body.

Carbon dioxide is a waste gas that must be removed from the body. It passes from

the bloodstream into the alveoli and is then breathed out by the lungs.

The right lung has three main areas (known as lobes) and the left lung has two

lobes. Many lung cancers start in the cells lining the bronchi and are called

Carcinomas of the bronchus or bronchogenic Carcinomas.

Lung Cancer

Lung cancer is the leading cause of cancer deaths in the United States, among

both men and women. It claims more lives than colon, prostate, lymph and breast cancer

co Lung cancer is the uncontrolled growth of abnormal cells in one or both of the lungs.

While normal lung tissue cells reproduce and develop into healthy lung tissue, these

abnormal cells reproduce rapidly and never grow into normal lung tissue. Lumps of

cancer cells (tumors) then form and disrupt the lung, making it difficult to function

properly.
 More than 87% of lung cancers are smoking related. However, not all smokers

develop lung cancer. Quitting smoking reduces an individual's risk significantly, although

former smokers remain at greater risk for lung cancer than people who never smoked.

Exposure to other carcinogens such as asbestos and radon gas also increases an

individual's risk, especially when combined with cigarette or cigar smoking.

Lung cancer is the second most common cancer, accounting for about one out of

five malignancies in men and one out of nine in women. Unfortunately, over the past

several years, while the incidence of lung cancer has gradually declined in men, it has

been rising alarmingly in women. In 1940 only seven women in 100,000 developed the

disease; today the rate is 42 in 100,000. And all the evidence points to smoking as the

cause. As one specialist in the field reports, “How long it takes to get cancer depends on

how may cigarettes you smoke a day.” However, studies prove that quitting smoking does

lower the risk.

Yet most of these lung cancer deaths could have been prevented. That's because

smoking accounts for nearly 90 percent of lung cancer cases. Although your risk of lung

cancer increases with the length of time and number of cigarettes you smoke, quitting

smoking, even after many years, can significantly reduce your chances of developing the

disease. Protecting yourself from exposure to other leading causes of lung cancer, such as

asbestos, radon and secondhand smoke, also decreases your risk.

 Prevention is critical because lung cancer usually isn't discovered until it's at an

advanced stage when the outlook for recovery is poor. Although the survival rates for ung

cancer have improved, they remain much lower than those of many other types of cancer.

Types of lung cancer

Generally cancer is divided into four stages: small and localised (stage one); has

spread into surrounding structures (stages two or three); or has spread to other parts of the

body (stage four). If the cancer has spread to distant parts of the body, this is known as

secondary cancer (or metastatic cancer).

The staging is different for small cell and for non-small cell cancers of the lung.

Primary lung cancer

Mesothelioma

Primary lung cancer

There are two main types of primary lung cancer which behave and respond to

treatment quite differently. They are:

• small cell lung cancer (SCLC)

• non-small cell lung cancer (NSCLC).

• Small cell lung cancer

About I in 5 lung cancers are small cell, the rest are non-small cell.

Small cell lung cancers are divided into just two stages. This is because small cell

lung cancer often spreads outside the lung quite early on. Even if the doctor cannot see

any spread of the cancer on your scans, it is likely that some cancer cells will have broken
away and travelled through the bloodstream or lymph system. To be safe, small cell lung

cancers are usually treated as though they have spread, whether any secondary cancer can

be seen or not.

The two stages of small cell lung cancers are:

 Limited disease – the cancer cells can be seen only in one lung, in nearby lymph

nodes, or in fluid around the lung (known as a pleural effusion).

 Extensive disease – it is clear that the cancer has spread outside the lung, within

the chest area or to other parts of the body.

Non-small cell cancer

There are three main types of non-small cell lung cancer. Sometimes it is not

possible to tell which type someone has. This is because when the cells are looked at

under a microscope they are not developed enough. The three types are:

Squamous cell carcinoma, , Adenocarcinoma, , Large cell carcinoma

Mesothelioma

A less common type of cancer that can affect the covering of the lungs is called

mesothelioma. It is a cancer of the membrane which covers the surface of the lungs and

lines the inside of the chest. It often occurs in people who have been exposed to asbestos.

Mesothelioma is not discussed here, but we have a separate section about this type

of cancer.

Non-small cell lung cancer

Non-small cell lung cancer is usually divided into four stages.

 Stage 1 cancer is very localised and has not spread to the lymph nodes. This

stage is divided in two:

  Stage 1A the cancer is no bigger than 3cm in size.

 Stage 1B the cancer is larger than 3cm, or it is growing into the main airway of

the lung (bronchus). The cancer may also have spread into the inner covering of

the lung (pleura) or made the lung partially collapse.

 Stage 2 non-small cell lung cancer is also divided in two:

 Stage 2A the cancer is small, measuring 3cm or less in size, and nearby

lymph nodes are affected.

 Stage 2B the cancer is larger than 3cm and in the nearby lymph nodes,

OR there is no cancer in the lymph nodes, but the tumour has grown into

the chest wall, the outer covering of the lung (pleura), the muscle layer

below the lungs (diaphragm), the covering of the heart, or it has made the

whole lung collapse.

 Stage 3 is also divided in two:

 Stage 3A the cancer is of any size and has spread into the lymph

nodes in the middle of the chest (mediastinum), but not to the

other side of the chest.

OR, the cancer has spread into tissue around the lung near to where the cancer started.

This can be into the chest wall, the covering of the lung (pleura), the middle of the chest

(mediastinum) or other lymph nodes close to the affected lung.

 Stage 3B the cancer has spread to lymph nodes on either side of the chest or

above either collar bone.

 Stage 4 lung cancer has spread to a distant part of the body, such as the liver or

the brain.
Causes of lung cancer

Lungs are two large, spongy organs shaped something like an upside-down

butterfly. Every time you inhale, air is carried through the windpipe to your lungs in two

major airways (bronchi). Inside your lungs, the bronchi subdivide over 15 times into a

million smaller airways (bronchioles), which finally end in clusters of tiny air sacs called

alveoli. Within the air sacs, oxygen is absorbed into your bloodstream and carbon

dioxide- a waste product of metabolism is released.

Smoking , Asbestos and Radon gas

Other causes

Smoking, Anatomy of a Cigarette and ConventionalCigarette

Tobacco

Cigarette smoking is known to be the cause of most lung cancers. Lung cancer

can also develop in people who do not smoke, although this is much rarer. The risk of

developing lung cancer increases with the number of cigarettes smoked, and if people

start to smoke at a young age. Filtered and low tar cigarettes may slightly reduce a

person’s risk of developing cancer, but it is still far greater than that of a non-smoker.

Leading Causes of Lung Cancer

 Cigarette smoking is the main cause of lung cancer. Tobacco smoke contains more

than 3,500 chemicals, at least 40 of which are known carcinogens. Cigarettes also contain

more than 30 toxic metals, including nickel and cadmium, as well as radioactive

compounds.

Lung cancer that begins in the lungs (primary lung cancer) is uncommon in

nonsmokers, but cancer of the breast, colon, prostate, testicle, kidney, thyroid, bone or

other organs may spread to the lungs. In that case, the cancer is still referred to by the

name of the organ in which it originated, rather than being called lung cancer. There's no

connection between smoking and the spread of cancer cells to the lungs from other parts

of the body.

Symptoms of lung cancer

"Smoker's cough" that worsens

• Coughing up blood, even a small amount

• Chest pain

• Shortness of breath

• New onset of wheezing

• Repeated bouts of pneumonia or bronchitis

• Hoarseness that lasts more than two weeks

• a continuing cough, or change in a long-standing cough

• a chest infection that does not get better

• increasing breathlessness

• coughing up blood-stained phlegm (sputum)

 • a hoarse voice

• a dull ache, or a sharp pain, when you cough or take a deep breath

• loss of appetite and loss of weight

• difficulty swallowing

• excessive tiredness (fatigue) and lethargy.

Lung cancer also may cause fatigue, loss of appetite and weight loss. If it has

spread to other parts of your body (metastasized), you may have headaches or bone pain.

If you have any of the above symptoms, it is important to have them checked by

your doctor, but any of these symptoms may be caused by illnesses other than cancer.

Treatment of lung cancer

Small cell lung cancer

Chemotherapy

Is the main treatment for small cell lung cancer. In many people, chemotherapy

for small cell lung cancer will enable them to live for longer, with better control of

symptoms. Chemotherapy may be given on its own, or before radiotherapy. Sometimes

chemotherapy and radiotherapy are given at the same time: this is known as

chemoradiation.

Surgery

Is not usually used to treat small cell cancer, except if the cancer is found very

early. This is because the cancer has usually spread to other parts of the body before

being diagnosed, even if it cannot be seen on a scan. If an operation is possible,

chemotherapy or radiotherapy may be given after surgery to kill any possible remaining
cancer cells and reduce the risks of the cancer coming back. Giving treatment in this way

is known as adjuvant treatment.

RADIOTHERAPY

To make sure that the radiotherapy works as well as possible, it has to be carefully

planned. On your first few visits to the radiotherapy department you will be asked to lie

under a large machine called a simulator, which takes x-rays of the area to be treated.

Sometimes, a CT scanner can be used for the same purpose.

Side effects - Radiotherapy can cause general side effects, such as feeling sick (nausea),

tiredness, Skin care and Hair loss.. It can also cause flu-like symptoms for a few days, or

chest pain.

Treating lung cancer with chemotherapy

There are over 60 types of chemotherapy drug. Those most commonly used to

treat lung cancer include cisplatin, carboplatin, gemcitabine, vinorelbine, paclitaxel and

docetaxel.

Side effects - Chemotherapy can cause unpleasant side effects.The main side effects are

described here, along with some of the ways they can be reduced. Lowered resistance to

infection,Bruising or bleeding ,Anaemia (low number of red blood ,cells) ,Feeling sick ,

Sore mouth,Hair loss,Tiredness

The Prevention of Lung Cancer

Encouraging behavior modification is a significant first step to ultimately

reducing the high number of lung cancer deaths each year. Yet, that is only part of the
solution. On the latest research front, scientists are studying methods to actually prevent

the development of lung cancer through natural and synthetic materials. In addition,

researchers believe that legislation designed to dissuade people from starting to smoke,

coupled with efforts to help people quit, will have a positive impact on the number of

new lung cancer cases in the future.

Treating lung cancer with cancer growth inhibitors

On the surface of many types of cancer cells, are structures known as epidermal

growth factor receptors (EGFRs). The receptors allow epidermal growth factor ( a

particular protein present in the body) to attach to them. When the epidermal growth

factor (EGF) attaches to the receptor, it causes chemical processes inside the cell that

make it grow and divide more quickly than it should.

EGFR as receptor

Growth factors are proteins that control the everyday function of cells in the body.

However some diseases such as cancer and psoriasis are associated with abnormal

activity of these growth factor driven processes. One such growth factor is the epidermal

growth factor (EGF) which stimulates cells by binding to a large protein on the surface

called the 'epidermal growth factor receptor'. The EGF receptor was the first of its type to

be discovered and there has been intense interest and activity around the world to

understand the molecular details of its structure and the way it binds EGF

Epidermal Growth Factor Receptor

The epidermal growth factor (EGF) receptor is one of the first discovered growth

factor receptors. Despite extensive characterization of the receptor, much remains to be

determined about its mechanism of action. Several members of the Epithelial laboratory
have been part of a collaboration with members of the Walter and Eliza Hall Institute and

the Health Sciences and Nutrition division of the CSIRO determined the structure of a

substantial fragment of the extracellular domain of the EGF receptor together. One of its

ligands, the transforming growth factor alpha (TGF-alpha), is also present in this

structure. A specific binding site is the receptor you wish to study. All of the other

binding sites in the tissue would be nonspecific sites.

The protein - the epidermal growth factor (EGF) receptor - was detected on

cancer cells over 20 years ago and laboratories all over the world have been trying to

understand how it works ever since.

EGFR as a Target in Cancer Therapy

As described in the preceding sections, epidermal growth factor receptor (EGFR)

has been shown to play a critical role in regulating tumor cell growth, repair and survival,

angiogenesis, invasion, and metastasis, and is expressed in a significant percentage of

human tumors. Furthermore, EGFR expression is correlated with poor prognosis and

decreased survival in numerous cancers. Therefore, it has been postulated that agents

designed to block EGFR activity will inhibit phosphorylation and signal transduction,
resulting in multiple antitumor mechanisms, as well as enhancing chemotherapy and

radiotherapy antitumor effects.

The additive or synergistic activity of EGFR inhibitors with a variety of

chemotherapeutic agents and radiation therapy has been demonstrated in a number of

preclinical trials, against various tumor cell lines.

Possible mechanisms for this effect have been proposed. In the case of

chemotherapy, it has been suggested that EGFR inhibitors and cytotoxic therapy are

likely to augment apoptosis in malignant cells. The synergism of EGFR inhibitors and

radiation therapy may occur by various mechanisms, including variations in the cell

cycle, preventing DNA repair post-radiation, and the inhibition of key cellular signaling

during cell cycle arrest.

Ligands for Epidermal Growth Factor Receptor (EGFR)

IRESSA

Iressa is a new type of cancer treatment and is currently being developed. It is a

man-made chemical that is being used in research trials to treat some types of cancer. It is

also sometimes called ZD1839 or gefitinib.

Some trials have shown that iressa can partially shrink cancer tumours in some

patients with advanced cancer (cancer which has already spread) who have already

received standard treatments for their particular type of cancer. However the drug had no

effect on some patients in the trials. When a drug reduces the size of a tumour the effect

may not last and the tumour may increase in size again after a short time.

Curcumin

Inhibition of ligand-induced activation of epidermal growth factor receptor

tyrosine phosphorylation by curcumin. We explored the regulation of epidermal growth

factor (EGF)-mediated activation of EGF receptor (EGF-R) phosphorylation by

Curcumin (diferuloyl-methane), a recently identified kinase inhibitor, in cultured NIH

3T3 cells expressing human EGF-R. Treatment of cells with a saturating concentration of

EGF for 5-15 min induced increased EGF-R tyrosine phosphorylation by 4- to 11-fold

and this was inhibited in a dose- and time-dependent manner by up to 90% by Curcumin,

which also inhibited the growth of EGF-stimulated cells. There was no effect of

Curcumin treatment on the amount of surface expression of labeled EGF-R and inhibition

of EGF-mediated tyrosine phosphorylation of EGF-R by Curcumin was mediated by a

reversible mechanism. In addition, Curcumin also inhibited EGF-induced, but not

bradykinin-induced, calcium release. These findings demonstrate that curcumin is a

potent inhibitor of a growth stimulatory pathway, the ligand-induced activation of EGF-

R, and may potentially be useful in developing anti-proliferative strategies to control

tumor cell growth.

Purpose: In a search for alternative and preventive therapies for prostate cancer,

attention was focused on the ways in which Curcumin (Turmeric), used in food and

medicine in India for centuries, could interfere with the growth factor signaling pathways

in both androgen-dependent and androgen-independent prostate cancer cells, as

exemplified by the epidermal growth factor receptor (EGF-R) signaling.

How it works

Curcumin works by blocking (inhibiting) signals within the cancer cells, which

prevents a series of chemical reactions that cause the cell to grow and divide. It is known

as a signal transduction inhibitor. This process is described in detail below.

On the surface of many types of cancer cell are structures known as epidermal

growth factor receptors (EGFRs). The receptors allow epidermal growth factor (a

particular protein present in the body) to attach to them. When the epidermal growth
factor (EGF) attaches to the receptor, it causes a chemical called tyrosine kinase to trigger

chemical processes inside the cell to make it grow and divide.

Curcumin attaches itself to the EGF receptor inside the cell, which blocks the

activation of tyrosine kinase, and switches off the signals from the EGFR. It therefore has

the potential to stop the cancer cells from growing. It works in a different way to both

chemotherapy and hormonal therapy.

Curcumin is an EGFR tyrosine kinase inhibitor. It works by binding to the

intracellular enzyme (tyrosine kinase) of the EGFR to directly block signals turned on by

triggers outside or inside the cell.

The activity of epidermal growth factor and its receptor, the EGFR, have been

identified as key drivers in the process of cell growth and replication. Heightened activity

at the EGF receptor, whether caused by an increase in the concentration of ligand around

the cell, an increase in receptor numbers or a decrease in receptor turnover or receptor

mutation, can lead to an increase in the drive for the cell to replicate. There is now a body

of evidence to show that the EGFR-mediated drive is increased in a wide variety of solid

tumours, including non-small cell lung cancer, prostate cancer, breast cancer, gastric

cancer, colon cancer, ovarian cancer and tumours of the head and neck.

The mechanism of the clinical antitumor action of curcumin is not fully

characterized. Curcumin inhibits the intracellular phosphorylation of numerous tyrosine

kinases associated with transmembrane cell surface receptors, including the tyrosine

kinases associated with the epidermal growth factor receptor (EGFR-TK). EGFR is

expressed on the cell surface of many normal cells and cancer cells

Curcumin for Cancer

 Previous trials have shown that in people whose cancer cells have many EGF

receptors the cancer may be more likely to develop quickly and also more likely to spread

to other parts of the body (metastasise). EGF receptors are found on many types of cancer

cells including non-small cell lung cancer, breast cancer, cancer of the bowel (colon and

rectum) and prostate cancer. Theoretically iressa could be used to treat any of these types

of cancer, but has so far been shown to be most effective against non-small cell lung

cancer. Current trials will show which other types of cancer it is active against.

Possible side effects

Curcumin does not appear to cause many side effects. So far, the main side effects

have been:

Diarrhoea: This can usually be easily controlled with medicine but tell your doctor if it

is severe or persistent. It is important to drink plenty of fluids if you do have diarrhoea.

An acne-like rash: This may be sore and itchy and your doctor can prescribe medicines

to help. The side effects are rarely severe.

Turmeric in India

India has a rich history of using plants for medicinal purposes. Turmeric

(Curcuma longa L.) is a medicinal plant extensively used in Ayurveda, Unani and Siddha

medicine as home remedy for various diseases (Ammon and Wahl, 1991; Eigner and

Scholz, 1999). C. longa L., botanically related to ginger (family: Zingiberaceae), is a

perennial plant having a short stem with large oblong leaves and bears ovate, pyriform or

oblong rhizomes, which are often branched and brownish-yellow in color.(Agarwal et

al.,2005).Turmeric is used as a food additive, preservative and colouring agent in Asian

countries, including China and South East Asia. It is also considered as auspicious and is
a part of religious rituals. In old Hindu medicine, it is extensively used for the treatment

of sprains and swelling caused by injury (Ammon and Wahl, 1991). In recent times,

traditional Indian medicine uses turmeric powder for the treatment of biliary disorders,

anorexia, coryza, cough, diabetic wounds, hepatic disorders, rheumatism and sinusitis . In

China, C. longa is used for diseases associated with abdominal pains (Araujo and Leon,

2001). The colouring principle of turmeric is the main component of this plant which

comes from polyphenolic compound and is responsible for the anti-inflammatory

property (Ammon et al., 1992).

Fig:1 Curcumal longa L. Fig :2 Turmeric

Sources

Food Sources

Tumeric, is the dried ground rhizome of Curcuma longa L. (Joe et al., 2004). It is

used as a spice in Asian and Middle Eastern cuisines. Curcuminoids comprise about 2-9%

of turmeric (Lechtenberg et al., 2004).

Chemical composition of turmeric

Various chemical components of turmeric are summarized in the Table 1 here

below (Kapoor, 1990).

Table 1: Chemical composition of turmeric

Constituent Amount
Protein 6.3%
Fat 5.1%
Minerals 3.5%
Carbohydrates 69.4%
Moisture 13.1%
Essential oil 5.8%
α-phellandrene 1%
Sabinene 0.6%
Cineol 1%
Borneol 0.5%
Zingiberene 25%
Sesquiterpines 53%
Diferuloylmethane 3–4%
Curcumin (Diferuloylmethane) (3–4%) is responsible for the yellow colour, and

comprises curcumin I (94%), curcumin II (6%) and curcumin III (0.3%) (Ruby et al.,

1995). Demethoxy and bisdemethoxy derivatives of curcumin have also been isolated

(Fig :3) (Vopel et al., 1990). Curcumin was first isolated (Vogel and Pelletier, 1815) in
1815 and its chemical structure was determined by Roughley and Whiting in 1973. It has

a melting point at 176–177°C; forms a reddish-brown salt with alkali and is soluble in

ethanol, alkali, ketone, acetic acid and chloroform (Roughley and Whiting, 1973).

The active substance of turmeric is the polyphenol curcumin, also known as C.I.

75300 or Natural Yellow 3. Systematic chemical name is (1E,6E)-1,7-bis(4-hydroxy-3-

methoxyphenyl)-1,6-heptadiene-3,5-dione. It can exist at least in two tautomeric forms,

keto and enol (Fig : 4 & 5). The keto form is preferred in solid phase and the enol form in

solution. ( Roughley and Whiting, 1973).

Fig : 4 Curcumin Keto form Fig : 5 Curcumin Enol form

Biological activity of curcumin and its compounds

Curcumin and its derivatives and many other extracts from the rhizomes were

found to be bioactive. (Araujo and Leon, 2001). Curcumin has healing effect on both

aseptic and septic wounds in rats and rabbits (Gujral et al., 1953). Extensive literature

available on the biological activities of curcumin and some of the significances are

summarized in table :

Biological activity of Curcumin and its compounds

Compound/extract Biological activity Reference

Turmeric Powder Wound-healing Gujral et al., 1953
Ethanol extract Antiinflammatory Yegnanarayan et al., 1976

Hypolipemic Dixit et al., 1988

 Antitumour Kuttan et al., 1985

Antiprotozoan Dhar et al., 1968

Alcoholic extract Antibacterial Bhavani and Sreenivasa , 1979
Crude ether extract Antifungal Misra andd Sahu, 1977
Chloroform extract Antifungal Misra andd Sahu, 1977
Aqueous extract Antifertility Garg, 1974
Vlatile oil Antiinflammatory Chandra and Gupta, 1972

Antibacterial Bhavani and Sreenivasa , 1979

Antifungal Banerjee and Nigam, 1978

Curcumin Antibacterial Lutomski et al., 1974

Antiprotozoan Bhavani and Sreenivasa , 1979

Antiviral Mazumdar et al., 1995

Hypolipemic Rao et al., 1970

Hypoglycemic Blasiak et al., 1999

Anticoagulant Kosuge et al., 1985

Antioxdant Sharma et al., 1955-68

Antitumour Deeb et al., 2003; Chen et al., 1996.

Anticarcinogenic Chen and Huang, 1998

Metabolism and Bioavailability

Clinical trials in humans indicate that the systemic bioavailability of orally

administered curcumin is relatively low (Sharma et al., 1955-68). Curcumin is readily

conjugated in the intestine and liver to form curcumin glucuronides and curcumin sulfates

or reduced to hexahydrocurcumin . (Ireson et al., 2002). Curcumin metabolites may not

have the same biological activity as the parent compound. In one study, conjugated or

reduced metabolites of curcumin were less effective inhibitors of inflammatory enzyme

expression in cultured human colon cells than curcumin itself (Ireson et al., 2001) . In a

clinical trial conducted in Taiwan, serum curcumin concentrations peaked 1-2 hours after
an oral dose, and peak serum concentrations were 0.5, 0.6 and 1.8 micromoles/liter at

doses of 4, 6 and 8 g/day, respectively (Cheng et al., 2001). Curcumin could not be

detected in serum at lower doses than 4 g/day.

Pharmacological action of curcumin

Effect on cardiovascular system

Curcumin decreases the severity of pathological changes and thus protects from

damage caused by myocardial infarction (Nirmala and Puvanakrishnan, 1996). Curcumin

improves Ca2+-transport and its slippage from the cardiac muscle sarcoplasmic

reticulum, thereby raising the possibility of pharmacological interventions to correct the

defective Ca2+ homeostasis in the cardiac muscle (Sumbilla et al., 2002). Curcumin has

significant hypocholesteremic effect in hypercholesteremic rats (Patil and Srinivasan,

1971).

Effect on Nervous system

Curcumin and manganese complex of curcumin offer protective action against

vascular dementia by exerting antioxidant activity (Vajragupta et al., 2003; Thiyagarajan

and Sharma, 2004).

Anticoagulant activity

Curcumin shows anticoagulant activity by inhibiting collagen and adrenaline-

induced platelet aggregation in vitro as well as in vivo in rat thoracic aorta (Srivastava et

al., 1985)

Antidiabetic effect
 Curcumin prevents galactose-induced cataract formation at very low doses

Suryanarayan et al., 2003). Both turmeric and curcumin decrease blood sugar level in

alloxan-induced diabetes in rat (Arun and Nalini, 2002). Curcumin also decreases

advanced glycation end productsinduced complications in diabetes mellitus (Sajithlal et

al., 1998) .

Antibacterial activity

Both curcumin and the oil fraction suppress growth of several bacteria like

Streptococcus, Staphylococcus, Lactobacillus, etc. (Bhavani and Sreenivasa , 1979) . The

aqueous extract of turmeric rhizomes has antibacterial effects (Kumar et al., 2001).

Curcumin also prevents growth of Helicobacter pylori CagA+ strains in vitro (Mahady et

al., 2002).

Antifungal effect

Ether and chloroform extracts and oil of C. longa have antifungal effects

(Banerjee and Nigam, 1978, Misra andd Sahu, 1977, Apisariyakul et al., 1995). Crude

ethanol extract also possesses antifungal activity (Wuthi et al., 2000). Turmeric oil is also

active against Aspergillus flavus, A. parasiticus, Fusarium moniliforme and Penicillium

digitatum (Jayaprakasha, 2001).

Antiviral effect

Curcumin has been shown to have antiviral activity (Araujo and Leon, 2001). It

acts as an efficient inhibitor of Epstein-Barr virus (EBV) key activator Bam H fragment z

left frame 1 (BZLF1) protein transcription in Raji DR-LUC cells (Hergenhahn et al.,

2002). EBV inducers such as 12-0-tetradecanoylphorbol-13-acetate, sodium butyrate and

transforming growth factor-beta increase the level of BZLF1 m-RNA at 12–48 h after
treatment in these cells, which is effectively blocked by curcumin (Hergenhahn et al.,

2002). Most importantly, curcumin also shows anti-HIV (human immunodeficiency

virus) activity by inhibiting the HIV-1 integrase needed for viral replication (Mazumdar

et al., 1995, De Clercq, 2000). It also inhibits UV light induced HIV gene expression

(Taher et al., 2003). Thus curcumin and its analogues may have the potential for novel

drug development against HIV.

Antivenom effect

Ar-turmerone, isolated from C. longa, neutralizes both hemorrhagic activity of

Bothrops venom and 70% lethal effect of Crotalus venom in mice (Araujo and Leon,

2001). It acts as an enzymatic inhibitor of venom enzymes with proteolytic activities

(Ferreira et al., 1992).

Pharmacokinetic studies on curcumin

Curcumin, when given orally or intraperitoneally to rats, is mostly egested in the

faeces and only a little in the urine (Wahlstrom and Blennow, 1978; Ravindranath and

Chandrasekhar, 1980). Only traces of curcumin are found in the blood from the heart,

liver and kidney. Curcumin, when added to isolated hepatocytes, is quickly metabolized

and the major biliary metabolites are glucuronides of tetrahydrocurcumin and

hexahydrocurcumin (Pan et al., 1999, Holder et al., 1978) Curcumin, after Metabolism in

the liver is mainly excreted through bile.

Anticarcinogenic effect induction of apoptosis

Curcumin acts as a potent anticarcinogenic compound. Among various

mechanisms, induction of apoptosis plays an important role in its anticarcinogenic effect.

It induces Apoptosis and inhibits cell-cycle progression, both of which are instrumental in
preventing cancerous cell growth in rat aortic smooth muscle cells (Chen and Huang,

1998). The antiproliferative effect is mediated partly through inhibition of protein

tyrosine kinase and c-myc mRNA expression and the apoptotic effect may partly be

mediated through inhibition of protein tyrosine kinase, protein kinase C, c-myc mRNA

expression and bcl-2 mRNA expression (Chen and Huang, 1998). Curcumin induces

apoptotic cell death by DNA-damage in human cancer cell lines, TK-10, MCF-7 and

UACC-62 by acting as topoisomerase II poison (Martin, 2003). Recently, curcumin has

been shown to cause apoptosis in mouse neuro 2a cells by impairing the ubiquitin–

proteasome system through the mitochondrial pathway (Jana et al., 2004). Curcumin

causes rapid decrease in mitochondrial membrane potential and release of cytochrome c

to activate caspase 9 and caspase 3 for apoptotic cell death (Jana et al., 2004). Recently,

an interesting observation was made regarding curcumin-induced apoptosis in human

colon cancer cell and role of heat shock proteins (hsp) thereon (Rashmi et al., 2004). In

this study, SW480 cells were transfected with hsp 70 cDNA in either the sense or

antisense orientation and stable clones were selected and tested for their sensitivity to

curcumin. Curcumin was found to be ineffective to cause apoptosis in cells having hsp

70, while cells harbouring antisense hsp 70 were highly sensitive to apoptosis by

curcumin as measured by nuclear condensation, mitochondrial transmembrane potential,

release of cytochrome c, activation of caspase 3 and caspase 9 and other parameters for

apoptosis (Rashmi et al., 2004). Expression of glutathione S-transferase P1-1 (GSTP1-1)

is correlated to carcinogenesis and curcumin has been shown to induce apoptosis in K562

leukaemia cells by inhibiting the expression of GSTP1-1 at transcription level (Duvoix et

a, 2003). The mechanism of curcumin-induced apoptosis has also been studied in Caki
cells, where curcumin causes apoptosis through down regulation of Bcl-XL and IAP,

release of cytochrome c and inhibition of Akt, which are markedly blocked by

Nacetylcysteine, indicating a role of ROS in curcumininduced cell death (Woo et al.,

2003). In LNCaP prostrate cancer cells, curcumin induces apoptosis by enhancing tumour

necrosis factor-related apoptosis-inducing ligand (TRAIL) (Deeb et al, 2003). The

combined treatment of the cell with Curcumin and TRAIL induces DNA fragmentation,

cleavage of procaspase 3, 8 and 9, truncation of Bid and release of cytochrome c from

mitochondria, indicating involvement of both external receptor-mediated and internal

chemical-induced apoptosis in these cells (Deeb et al., 2003) . In colorectal carcinoma

cell line, Curcumin delays apoptosis along with the arrest of cell cycle at G1 phase (Chen

et al., 1996). Curcumin also reduces P53 gene expression, which is accompanied with the

induction of HSP-70 gene through initial depletion (Chen et al., 1996) of intracellular

Ca2+. Curcumin also produces nonselective inhibition of proliferation in several

leukaemia, nontransformed haematopoietic progenitor cells and fibroblast cell lines

(Gautam et al., 1998). That curcumin induces apoptosis and large-scale DNA

fragmentation has also been observed in Vg9Vd2+ T cells through inhibition of

isopentenyl pyrophosphate-induced NFkB activation, proliferation and chemokine

production (Cipriani et al., 2001). Curcumin induces apoptosis in human leukaemia HL-

60 cells, which is blocked by some antioxidants (Kuo et al,. 1996). Colon carcinoma is

also prevented by curcumin through arrest of cell-cycle progression independent of

inhibition of prostaglandin synthesis (Hanif et al., 1997). Curcumin suppresses human

breast carcinoma through multiple pathways. Its antiproliferative effect is estrogen

dependent in ER (estrogen receptor)-positive MCF-7 cells and estrogen-independent in

ER-negative MDA-MB-231 cells (Shao et al,.2002). Curcumin also down regulates

matrix metalloproteinase (MMP)-2 and up regulates tissue inhibitor of metalloproteinase

(TIMP)-1, two common effector molecules involved in cell invasion (Shao et al,.2002). It

also induces apoptosis through P53-dependent Bax induction in human breast cancer

cells (Choudhuri et al., 2002). However, Curcumin affects different cell lines differently.

Whereas leukaemia, breast, colon, hepatocellular and ovarian carcinoma cells undergo

apoptosis in the presence of Curcumin, lung, prostate, kidney, cervix and CNS

malignancies and melanoma cells show resistance to cytotoxic effect of Curcumin (Khar

et al., 2001). Curcumin also suppresses tumour growth through various pathways. Nitric

oxide (NO) and its derivatives play a major role in tumour promotion. Curcumin inhibits

iNOS and COX-2 production (Brouet and Ohshima, 1995) by suppression of NFkB

activation (Surh et al., 2001). Curcumin also increases NO production in NK cells after

prolonged treatment, culminating in a stronger tumouricidal effect (Bhaumik et al.,

2000). Curcumin also induces apoptosis in AK-5 tumour cells through up regulation

(Khar et al., 1999) of caspase-3. Reports also exist indicating that curcumin blocks

dexamethasoneinduced apoptosis of rat thymocytes (Sikora et al., 1997, Jaruga et al.,

1998). Recently, in Jurkat cells, curcumin has been shown to prevent glutathione

depletion, thus protecting cells from caspase-3 activation and oligonucleosomal DNA

fragmentation (Piwocka et al., 2001). Curcumin also inhibits proliferation of rat

thymocytes (Sikora et al., 1997) .These strongly imply that cell growth and cell death

share a common pathway at some point and that curcumin affects a common step,

presumably involving modulation of AP-1 transcription factor (Sikora et al., 1997;

Piwocka et al., 2001).

Induction of Cell Cycle Arrest and Apoptosis

After a cell divides, it passes through a sequence of stages collectively known as

the cell cycle before it can divide again. Following DNA damage, the cell cycle can be

transiently arrested to allow for DNA repair or activation of pathways leading to cell

death (apoptosis) if the damage cannot be repaired (Stewart et al., 2003). Defective cell

cycle regulation may result in the propagation of mutations that contribute to the

development of cancer. Curcumin has been found to induce cell cycle arrest and

apoptosis in a variety of cancer cell lines grown in culture (Duvoix et al., 2005). The

mechanisms by which curcumin induces apoptosis are varied but may include inhibitory

effects on several cell signaling pathways. However, not all studies have found that

curcumin induces apoptosis in cancer cells. Curcumin inhibited apoptosis induced by the

tumor suppressor protein p53 in cultured human colon cancer cells (Moos et al., 2004;

Tsvetkov et al., 2005), and one study found that Curcumin inhibited apoptosis induced

by several chemotherapeutic agents in cultured breast cancer cells at concentrations of 1-

10 micromoles/liter (Somasundaram et al., 2002).

Inhibition of Tumor Invasion and Angiogenesis

Cancerous cells invade normal tissue aided by enzymes called matrix

metalloproteinases. Curcumin has been found to inhibit the activity of several matrix

metalloproteinases in cell culture studies (Banerji et al., 2004; Ohashi et al., 2003;

Menon et al., 1999). Invasive tumors must also develop new blood vessels to fuel their

rapid growth by a process known as angiogenesis. Curcumin has been found to inhibit

angiogenesis in cultured vascular endothelial cells (Thaloor et al., 1998) and in an animal

model (Arbiser et al., 1998).

Disease Prevention

Cancer

The ability of curcumin to induce apoptosis in cultured cancer cells by several

different mechanisms has generated scientific interest in the potential for curcumin to

prevent some types of cancer (Sharma et al., 1955-68). Oral curcumin administration has

been found to inhibit the development of chemically-induced cancer in animal models of

oral (Krishnaswamy et al., 1998; Li et al ., 2002), stomach (Ikezaki et al., 2001; Huang

et al., 1994), liver (Chuang et al., 2000), and colon (Pereira et al., 1996; Rao et al.,

1995; Kawamori et al., 1999) cancer. ApcMin/+ mice have a mutation in the Apc

(adenomatous polyposis coli) gene similar to that in humans with familial adenomatous

polyposis, a genetic condition that is characterized by the development of numerous

colorectal adenomas (polyps) and a high risk for colorectal cancer. Oral curcumin

administration has been found to inhibit the development of intestinal adenomas in

ApcMin/+ mice (Mahmoud et al., 2000; Perkins et al., 2002). In contrast, oral curcumin

administration has not consistently been found to inhibit the development of mammary

(breast) cancer in animal models (Pereira et al., 1996; Singletary et al., 1998; Huang et

al., 1998).

Although the results of animal studies are promising, particularly with respect to

colorectal cancer, there is presently little evidence that high intakes of Curcumin or

turmeric are associated with decreased cancer risk in humans. A phase I clinical trial

examined the effects of oral Curcumin supplementation up to 8 g/day for 3 months in

patients with precancerous lesions of the mouth (oral leukoplakia), cervix (high grade

cervical intraepithelial neoplasia), skin (squamous carcinoma in situ) or stomach

(intestinal metaplasia) (Cheng et al., 2001). Histologic improvement on biopsy was

observed in 2 out of 7 patients with oral leukoplakia, 1 out of 4 patients with cervical

intraepithelial neoplasia, 2 out of 6 patients with squamous carcinoma in situ and 1 out of

6 patients with intestinal metaplasia. However, cancer developed in 1 out of 7 patients

with oral leukoplakia and 1 out of 4 patients with cervical intraepithelial neoplasia by the

end of the treatment period. This study was designed mainly to examine the

bioavailability and safety of oral Ccurcumin, and interpretation of its results is limited by

the lack of a control group for comparison. As a result of the promising findings in

animal studies, several controlled clinical trials in humans designed to evaluate the effect

of oral curcumin supplementation on precancerous colorectal lesions, such as adenomas,

are under way ( National Institutes of Health. Clinical Trials.gov. 2005 ).

Drug Interactions

Curcumin has been found to inhibit platelet aggregation in vitro (Shah et al.,

1999; Srivastava et al., 1995), suggesting a potential for Curcumin supplementation to

increase the risk of bleeding in people taking anticoagulant or antiplatelet medications,

such as aspirin, clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox),

heparin, ticlopidine (Ticlid) and warfarin (Coumadin). In cultured breast cancer cells,

curcumin inhibited apoptosis induced by the chemotherapeutic agents campothecin,

mechlorethamine and doxorubicin at concentrations of 1-10 micromolesl/liter

(Somasundaram et al., 2002). In an animal model of breast cancer, dietary Curcumin

inhibited cyclophosphamide-induced tumor regression. Although it is not known whether

oral Curcumin administration will result in breast tissue concentrations that are high

enough to inhibit cancer chemotherapeutic agents in humans (Garcea et al., 2004). it may

be advisable for women undergoing chemotherapy for breast cancer to avoid curcumin

supplements ( Somasundaram et al., 2002). Some Curcumin supplements also contain

piperine, for the purpose of increasing the bioavailability of Curcumin. However,

piperine may also increase the bioavailability and slow the elimination of a number of

drugs, including phenytoin (Dilantin), propranolol (Inderal) and theophylline (Bano et al.,

1991; Velpandian et al., 2001).

Due to the many natural medicinal qualities of Curcumin in medicine and

pharmacology the present study has been undertaken to design a structure based drug of

curcumin componds and choose the best drug by employing few basic bioinformatic

tools.

Computer aided drug designing

CADD methods and bioinformatics tools offer significant benefits for drug
discovery programs.
Cost Savings.
The Tufts Report suggests that the cost of drug discovery and development has
reached $800 million for each drug successfully brought to market. Many
biopharmaceutical companies now use computational methods and bioinformatics tools
to reduce this cost burden. Virtual screening, lead optimization and predictions of
bioavailability and bioactivity can help guide experimental research. Only the most
promising experimental lines of inquiry can be followed and experimental dead-ends can
be avoided early based on the results of CADD simulations.
Time-to-Market.
 The predictive power of CADD can help drug research programs choose only the
most promising drug candidates. By focusing drug research on specific lead candidates
and avoiding potential “dead-end” compounds, biopharmaceutical companies can get
drugs to market more quickly.
Insight.
One of the non-quantifiable benefits of CADD and the use of bioinformatics tools
is the deep insight that researchers acquire about drug-receptor interactions. Molecular
models of drug compounds can reveal intricate, atomic scale binding properties that are
difficult to envision in any other way. When we show researchers new molecular models
of their putative drug compounds, their protein targets and how the two bind together,
they often come up with new ideas on how to modify the drug compounds for improved
fit. This is an intangible benefit that can help design research programs.
CADD and bioinformatics together are a powerful combination in drug research
and development.

AIM AND SCOPE OF THE WORK

Curcuma longa is a ginger-like plant that grows in tropical regions. The roots

contain a bright yellow substance (turmeric) that contains curcumin and other

curcuminoids. Turmeric has been used in Ayurvedic and Chinese medicine for centuries.

But it's only within the past few years that the extraordinary actions of curcumin against

cancer have been scientifically documented. Among it’s many

Curcumin can stop cancer in its earliest stages, long before it's detectable. It

works at the level of the cell. One of the things it does is to tell damaged cells to self-

destruct so they won't keep multiplying. The process is called "apoptosis" and it's the

body's way of destroying abnormal cells that can become cancerous. Cancer cells can
circumvent the process, but curcumin can override them and send "self-destruct" signals

to many different types of cancer cells. Curcumin does not induce apoptosis of healthy

cells, only cancerous ones. It identifies cancer cells by their abnormal chemistry.

Unfortunately, it doesn't work in all types of cancer, but Indian researchers may have

figured out why. Their findings, published in the Journal of Biological Chemistry, may

lead to ways of making most types of cancer susceptible to curcumin's effects.

The epidermal growth factor receptor (EGFR) is under investigation as a

therapeutic target for cancers. Lung cancer cell lines are variably dependent on autocrine

stimulation of EGFR since it has a role in signal transduction, which results in cell

proliferation, metastasis, angiogenesis, and dedifferentiation. We therefore examined the

effects of a selective EGFR tyrosine kinase inhibitor zd1839 (iressa), on proliferation and

survival of lung cancer cell lines by using docking software tools (vega zz).Using

chemskecth I have designed 3 new drug molecules(iressa A,iressa B & Iressa C ) on the

basis of iressa drug, and compared the commercial iressa drug and natural curcumin

drug by docking it on EGFR protein by using vega ZZ software on the basis of energy

score A found that curcumin will be the best inhibitor than standard Iressa drug . Again

on comparing the ADME properties of commercial drug iressa , modified drugs and

natural curcumin drug ( by using ADME tool ),I found that this natural curcumin drug

will act as more efficient drug to inhibit EGFR protein and stop signal transduction which

is the major step in causing lung cancer.This natural curcumin drug has to be proved in

wet lab also. It can be used further in clinical trials to test it effectiveness and for social

benefit.
 The objective of this project is to uncover some of the aspects of lung cancer,

which will subsequently contribute to the ongoing research.

The study, proposed herewith, adds weight to the growing body of science linking

consumption of the spice to decreased risk of certain cancers, like Lung cancer. "Our

observations help to… identify a mechanism by which Curcumin functions as an

anticancer agent.

The anti-cancer effects of spices from curcumin to red chili pepper capsaicin have

been consistently researched. The lowest incidence of both Lung and Brest cancers is

observed in Asia and the Far East, in particular India and China, and this has been linked

to high dietary intake of compounds like turmeric.

Using PC-3 human prostate cancer cell lines grown in vitro, the researchers

observed that curcumin decreased the expression of a protein associated with malignant

tumor formation called MDM2. The turmeric extract was also found to increase the

expression of a protein that increases programmed cell death (apoptosis) of the cancer

cells.

To test the efficacy of curcumin in vivo, the researchers grafter PC-3 prostate

cancer cells into a group of nude mice, and then assigned to receive either curcumin or

cottonseed oil (placebo) orally for five days per week for four weeks.

The curcumin-fed mice were further divided into three groups with five animals

per group. One group continued to receive only curcumin supplements, while the others

received curcumin in conjunction with the chemotherapy agent gemcitabine or curcumin

in conjunction with radiotherapy.

 "Curcumin inhibited growth of PC3 xenografts and enhanced the antitumor

effects of gemcitabine and radiation. In these tumors, curcumin reduced the expression of

MDM2," wrote the researchers.

"Down-regulation of the MDM2 oncogene by curcumin is a novel mechanism of

action that may be essential for its chemopreventive and chemotherapeutic effects," they

concluded.

Ricardo Sanchez-Ortiz, MD, who was not involved in the study, said: "These

exciting data suggest that this dietary supplement should be studied in combination with

traditional forms of chemotherapy or radiotherapy in tumours dependent on the MDM2

pathway."

Several studies suggested that curcumin inhibits growth of malignant cells via

inhibition of cyclooxygenase-2 (COX-2) activity. Other studies indicated that epidermal

growth factor receptor (EGFR) is also inhibited by curcumin in vitro and in vivo.

Moreover, recent investigations revealed an intracellular cross-talk between EGFR

signaling and the COX-2 pathway. Our aim was to evaluate whether the curcumin

inhibitory effect on the survival of cancer cells is associated with simultaneous down-

regulation of EGFR and inhibition of Erk1/2 (extra-cellular signal regulated kinase)

signaling pathway.: Lung and pancreas adenocarcinoma cell lines co-expressing EGFR

(PC-14 and p34, respectively) and those expressing EGFR but deficient in COX-2

(H1299 and Panc-1, respectively) were exposed for 72 h to curcumin (0-50 microM).

Cell viability was assessed by the XTT assay. Curcumin's inhibitory effect on survival

and apoptosis of lung and pancreatic adenocarcinoma cell lines was significantly higher

in the COX-2-expressing cells than in the COX-2-deficient cells. In the p34 and PC-14
cells, curcumin decreased COX-2, EGFR and p-Erk1/2 expressions in a dose-dependent

manner.

The following observations are Aimed

 To prove Curcumin co-inhibits EGFR expression and decreased Erk1/2

activity.

 To Prove this inhibition was associated with decreased survival and

enhanced induction of apoptosis in lung and pancreatic adenocarcinoma

cells.

SYSTEMS AND METHODS

DESCRIPTION OF DATABASES USED

PUBCHEM
PubChem is a database of chemical molecules. The system is maintained by the
National Center for Biotechnology Information (NCBI), a component of the National
Library of Medicine, which is part of the United States National Institutes of Health
(NIH). PubChem can be accessed for free through a web user interface. Millions of
compound structures and descriptive datasets can be freely downloaded via FTP.
PubChem contains substance descriptions and small molecules with fewer than 1000
atoms and 1000 bonds. because they claim it competes with their Chemical Abstracts
Service. More than 80 database vendors contribute to the growing PubChem database.
PUBMED
 PubMed is a free search engine for accessing the MEDLINE database of citations
and abstracts of biomedical research articles. The core subject is medicine, and PubMed
covers fields related to medicine, such as nursing and other allied health disciplines. It
also provides very full coverage of the related biomedical sciences, such as biochemistry
and cell biology. It is offered by the United States National Library of Medicine at the
National Institutes of Health as part of the Entrez information retrieval system. As with
other indexes, the inclusion of an article or journal in PubMed is not endorsement. In
2007 MEDLINE contained over 17,000,000 records from more than 5,000 journals
published in the United States and more than 80 other countries primarily from 1950
onwards.
DRUGBANK
The Drug Bank database is a unique bioinformatics and chem. informatics
resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical)
data with comprehensive drug target (i.e. sequence, structure, and pathway) information.
The database contains nearly 4800 drug entries including >1,480 FDA-approved small
molecule drugs, 128 FDA-approved biotech (protein/peptide) drugs, 71 nutraceuticals
and >3,200 experimental drugs. Additionally, more than 2,500 non-redundant protein (i.e.
drug target) sequences are linked to these FDA approved drug entries.
PDB
The Protein Data Bank (PDB) is a repository for 3-D structural data of proteins
and nucleic acids. These data, typically obtained by X-ray crystallography or NMR
spectroscopy and submitted by biologists and biochemists from around the world, are
released into the public domain, and can be accessed for free.
THERAPEUTIC TARGET DATABASE (TTD)
A database to provide information about the known and explored therapeutic
protein and nucleic acid targets, the targeted disease, pathway information and the
corresponding drugs/ligands directed at each of these targets. Also included in this
database are links to relevant databases that contain information about the function,
sequence, 3D structure, ligand binding properties, enzyme nomenclature and related
literatures of each target. This database currently contains 1535 targets and 2107
drugs/ligands.
DESCRIPTION OF TOOLS USED
CHEMSKETCH
ACD/ChemSketch is an advanced chemical drawing tool and is the accepted
interface into the industry's best NMR and molecular property predictions, nomenclature,
and analytical data handling software. ACD/ChemSketch is also available as freeware,
with functionalities that are highly competitive with other popular commercial software
packages. The freeware contains tools for 2D structure cleaning, 3D optimization and
viewing, InChI generation and conversion, drawing of polymers, organometallics, and
Markush structures—capabilties which are not even included in some of the commercial
packages from other software producers. Also included is an IUPAC systematic naming
capability for molecules with fewer than 50 atoms and 3 rings. The capabilities of
ACD/ChemSketch can be further extended and customized by programming.
VEGA
VEGA ZZ is the evolution of the well known VEGA OpenGL package and
includes several new features and enhancements making your research jobs very easy.
VEGA was originally developed to create a bridge between most of the molecular
software packages only, but in the years, enhancing its features, it's evolved to a complete
molecular modelling suite. This software is FREE for non-profit academic uses.
CORINA
CORINA is a program for the fast and efficient generation of high-quality three-
dimensional molecular models .Fast and Efficient Generation of High-Quality Three-
Dimensional Molecular Models. CORINA software generates low energy conformation,
three-dimensional atomic coordinates from a molecule’s connection table data. CORINA
converts a higher rate of two-dimensional structures than other programs, and is
applicable to the entire range of organic chemistry as well as many organometallic
compounds. CORINA will generate 3D coordinates for the given structure. A new page
will be generated showing the 3D molecular model if you have RASMOL, CHIME, or
some similar program installed on your computer).
RASMOL
RasMol is an excellent and free molecular viewer available for Windows,
Macintosh and UNIX platforms. RasMol is a computer program written for molecular
graphics visualization intended and used primarily for the depiction and exploration of
biological macromolecule structures, such as those found in the Protein Data Bank. It was
originally developed by Roger Sayle in the early 90s.
ADMETOX
ADMETox is poor absorption, distribution, metabolism, elimination (ADME) and

toxicity filtering for small compounds. Based on a set of elementary rules.

Step-wise protocol adopted in the present study

Literature search:

 log on to www.pubmed.com

 Enter the keywords of the concepts to be searched in the search box

provided

 click the ‘search’ Button

 From the list of hits displayed , select the articles of interest

 save the contents.

Retrieving protein structure from protein data bank (pdb):

 Go to the home page of protein data bank(pdb) with the help of www.rcsb.org/pdb

 type the protein name in advanced search column and click the “search” button

 In the next page the hits of protein structure will be visible

 From the list of hits select ids whichever you need and click on id

 click on the download option which is present in left corner of the result page

 chose the pdb file format and click

 save the protein structure as pdb file format and the structure visualize by rasmol

off line tool

Retrieving drug compound from the pubchem compound database

 Go to the home page of pubchem compound database with the help of

www.genome.jp/kegg/drug .

 Enter the drug compound name in the search column

 click on “Go” button

 In the next page hits of drug compound will be visible

 From the list of hits displayed, select the chemical compound of interest

and click on the respective hit

 in the result page chemical compound name, molecular weight, smiles

(simplified molecular input line entry specificaion) of structure will be

there.

 Save the smiles of selected drug compound

2D TO 3D Conversion of drug compound

• Go to the home page of coina online server with help of

http://www.molecular-networks.com/online_demos/corina_demo.html

• Paste your input (smiles ) which are downloaded from pubchem compund

database

• click “submit” button

• In the next page select download file option and click on it.

• save the 3D structure of drug

Modification of drug by using CHEMSKETCH software:

 • Go to Google home page and enter chemsketch in search colum click

“search”button

• select first option download acd/labs freeware and click on the option

• download the software by clicking the option chemsketch 10.0 freeware.

• select the structure of the drug ( ligand ) modify it .

• copy the modified drug compound as pdb coordinates and convert in to 3 d

structure by using dundee server.

• protein – ligand docking by using vega zz:

• Open the vegaZZ off line software

• Go to the file menu open protein structure and drug strucute

• Go the calculate option and click on “Escher “

• In the Escher page Load probe(drug) and target (protein) for docking

• click on “start” button

• Once docking is completed it can generate pdb file of solutions in appropriate

folder.

• interpret the result by using energy graph

• Calculate the score and the minimum conformation of the complex molecule

• Choose the best score (high score) of the complex molecule (protein- drug

molecule).

Protein structure retrieving

The target protein structure is retrieved from Protein data Bank .The wire frame

model of the Protein structure is visualized and analyzed by RasMol version 2.6.
Retrieving drug compound
The ligand drug compound is retrieved from the pubchem compound database.
The stick model of the drug compound is visualized and labeled by the RasMol
Version2.6
Modification of drug compound
The drug compound is modified by using chemsketch off line software. It helps to

draw molecules, reactions, and schematic diagrams, calculate chemical properties, and

design professional reports and presentations.

The structure of the drug compound is modified by using the buttons located on

the structure toolbar, Atoms toolbar and references toolbar and calculated the elemental

composition, formula, weight of the drawn structure(s), and chemical property of the

selected structure. By using this tool we can also Calculate the molar refractivity, molar

volume, index of refraction, surface tension, density, and some other physicochemical

properties for the selected structure.

Conversion of 3D structure of drug

The selected drug of 2D structure is converted in to 3D structure by using corina

server. The 3D structure of drug molecule is visualized and analyzed by the visualizing

tool RasMol version 2.6 .

Ligand-Receptor Docking

In compliance to the idea that every “lock” has a “key”, we can construct, search and

match various molecules to the active site of a receptor. The goal is to use knowledge of the

ligand and the receptor to make predictions if and how they will form a non-covalently

bonded complex.
 Here a ligand is a small organic molecule with a size of about 10 to 200 atoms. The

receptor is a protein, usually of a much larger size than the ligand. Predictions can be made as

to how the ligand and receptor will interact to form a complex. The computational approach

to this is called docking.

It can be assumed that for a complex formed by a native ligand and its receptor

corresponds to a state in which the free binding energy is minimal. With this knowledge the

docking problem becomes an energy minimization task to find the lowest free energy binding

mode for receptor and a putative ligand. In general, there are two aims of docking studies:

accurate structural modeling and correct prediction of activity.

Docking

Drug compounds are docked with the target protein molecule by using Vega zz .

Steps undertaken

Solution file:-extract solution file by using ESCHER NG commands. Solutions are

generated by docking inhibitors to target protein, once docking is completed we can generate

PDB file of solutions by using –s commands at ESCHER console and can interpret the result

by using energy graph.

• Calculate the score and the minimum conformation molecule:-Docking score

includes; Score, rms, bumps values, charges etc.

• Extract solution file as in step 2.

• Calculate the score and the minimum conformation molecule of both inhibitors.

• Compare the interaction energy with the help of interaction energy graph.

• Output lowest energy conformation of selected drug were found

• Comparative Analysis:-After generating the solution file of all drugs compare the
 score and minimum energy conformation molecule of all drugs.

• Find out the best drug having minimum energy conformation.

Docking steps involved in Vega ZZ ZZ

• Diffusion controlled encounter rate .

• Initial Michaelis complex .

• Desolvation of both inhibitor and binding site .

• Conformational changes of both inhibitor and binding site upon binding .

• Correct orientation between drug and receptor binding site .

Goals of Docking

• The docking process involves the prediction of ligand conformation and

orientation or posing within a targeted binding site.

• Characterize binding site - make an image of binding site with interaction points

.Orient ligand into binding site

• Evaluate strength of the interaction:-  G = G –( G +

bind complex ligand

G )
target

3) Estimating the binding affinity

• Searching for lead structures for protein targets

• Comparing a set of inhibitors

• Estimating the influence of modifications in lead structures

• De Novo Ligand Design

 • Design of targeted combinatorial libraries

4) Predicting the molecule complex

• Understanding the binding mode / principle

• Optimizing lead structures

Vega ZZ 2.0.5 Software for Docking

It is molecular modeling software and includes several new features and

enhancements making research jobs very easy. VegaZZ contains several features that are not

generally found in single software.

1) Basic principle and methods

ESCHER is a new docking procedure named as evaluation of surface

complimentarity, hydrogen bonding and electrostatic interaction in molecular recognition.

ESCHER consists of three modules that work in series to perform docking procedure.

ESCHER is a rigid docking program, written in C language.

The three modules and their work to perform docking are as following:

• SHAPES module : evaluates the geometric complementarity and produces a set of

rough solutions for the docking problem.

• BUMPS module : identifies molecular collisions within those solutions

• CHARGES module: third module evaluates their electrostatic complementarity

II) Usage

The required files to run ESCHER are the probe and the target in PDB format without

hydrogens . (TARGET and PROBE are the file names of the target and probe molecules).

Probe and target are the partners witch best orientation will be find by ESCHER maximizing

the attractive forces and minimizing the repulsions.

III) The ESCHER NG input & output file formats

Vega ZZ accepts mainly PDB, msf. Csr, .dat files as input to view the molecules.

ESCHER NG generates three types of output files that one can identify by the extension:

1. PDB:- It's the solution extracted with the -s option. It contains the probe only and it is

needed to open the target and the extracted files in preferred molecular graphic package if

you want analyze the complex.

Sol:- It's the output text file including the solutions. ESCHER NG creates two solutions files

named *_1.sol and *_2.sol. where * is the name of the target and the probe separated by a

dash (-). The first contains the all computed solutions, and the second contains the clustered

solution neglecting the out-layered scores.

Srf:- It's the surface file in Insight format

The above three files are generated in the directory that contain target and probe

molecules. To perform docking the both target and probe molecules should be in same

directory.

IV) The ESCHER NG outputs

After generating all the files .PDB, .sol, .srf. Solutions are extracted from .sol file by

using –s command. This option allows to extract the solutions from the ESCHER output file

(*_2.sol). The SOLUTION_ID is the solution number in the output file, and the trajectory is

used to save all the solutions generated by going to file/save trajectory as on VegaZZ tool

bar.To view the the result generated in solution file we can open the solution file in word pad.

The solution output file

 The solution output file contains some sections. Each section begins with a keyword

starting with the # character. The file format scheme is the following:

#ESCHERNG_VER

It’s file header and it's placed at the first line. This tag has got a version number

that identifies the type of the ESCHER output. At this time, the allowed version number

is 1. After the #ESCHER_VER tag the file can contain the date, user comments, etc

without limits in the number of lines.

#Solutions

In this section the calculated solutions are included. The first two lines are the column

labels for best user readability. Each subsequent line is a solution and the meaning of each

field is the following.

Column Description
Sol. Solution number.
Score Total score (high score = best complex).
Rms Root mean square.
Bumps Number of atom collisions between target and probe.
Chg. Total charge score.
Pos. Positive <-> negative charge score.
Neg. Positive <-> positive and negative <-> negative charge score.
Apo. Apolar <-> apolar score.
Pol. Apolar <-> polar score.
RotX X rotation.
RotY Y rotation.
RotZ Z rotation.
TransX X translation.
TransY Y translation.
TransZ Z translation.
Table: The Solution output file of ESCHER NG.

Prediction of drug properties using ADME Tox tool:

 A QSAR (Quantitative Structure-Activity Relationship) is a multivariate,
mathematical relationship between a set of 2D and 3D physico-chemical properties) and
biological activity. The QSAR relationship is expressed as a mathematical equation..
QSAR provide basic insight into structure-property relationships.
Building a QSAR equation, including:

• Entering molecules in a training set.

• Entering biological activity data.
• Entering molecular descriptors.
• Exploring the data.
• Generating a QSAR equation.
• Validating and saving the QSAR equation.
• Predicting activity of new molecules.

RESULT AND DISCUSSION

Protein Structure retrieving

The target protein epidermal growth factor receptor is retrived from Protein data
Bank .The PDB id of the epidermal growth factor receptor is 1MOX The Protein
structure is visualized by RasMol tool
Fig .1: Wire frame model of epidermal growth factor receptor
 Fig: 1. Shows the three dimensional molecular structure of Epidermal growth
factor receptor which is retrieved from protein data bank and viewed it in different forms
like wire frame model by using Rasmol molecular visualization tool . . Rasmol is
window-based tool. The wire frame model clearly shows the chemistry of epidermal
growth factor receptor, from this we can easily trace of the sequence.
Protein databank from RCSB or MMDB provides the 3D molecular structure
data. The name of the protein epidermal growth factor receptor is entered on pdb home
page at text box. After that the type of viewer ( Rasmol) is selected and finally clicked to
display. Then 3D protein structure and its data also download as a pdb file and analysed

Retrieving drug compounds

The ligand drug compounds are retrieved from the NCBI pubchem compound

database. The wireframe model of the drug compounds are visualized and labeled by the

RasMol version 2.6

Fig: 2. Structure of Iressa Fig: 3. Structure of Curcumin

 Fig 2 : shows the structure of Iressa drug which is a man-made chemical that is

being used in research trials to treat some types of cancer. It is also sometimes called

gefitinib. Iressa drug Is retrieved from NCBI pubchem compound database

Fig :3. shows the structure of Curcumin which is retrived from Ncbi pubchem

compound databank

Modification and 3D conversion of drug compound

Fig 4: Modified drug Iressa A

 3D structure of Iressa A

Fig 4: shows the modified Iressa drug A. the structure of Iressa has drawn in
chemsketch software and chlorine of standard Iressa drug is replaced by bromide then it
is named as Iressa A. The figure also shows the SMILES (simplified molecule input line
entry specification) and general properties of modified drug Iressa A.. molecular formula
of modified drug Iressa A is C22H24BrFN4O3, formula weight is 491.353, Nominal mass is
490 da, Avarae mass is 491.4 and surface tension 58.8 .

Fig : 5 : Modified drug Iressa B

 Fig 5: shows the modified Iressa drug B. the structure of Iressa has drawn in

chemsketch software and chlorine and fluorine of standard Iressa drug is replaced by

bromide and Iodine then it is named as Iressa B . The figure also shows the SMILES

(simplified molecule input line entry specification) and general properties of modified

drug Iressa A.. Molecular formula of modified drug Iressa B is C 22H24BrIN4O3, formula

weight is 599.26, Nominal mass is 598 da, Avarae mass is 599.4 and surface tension 59.9

Fig : 6. Modified drug iressa C

 3D structure of Iressa B

Structure of curcumin

Fig 6: shows the modified Iressa drug C. the structure of Iressa has drawn in

chemsketch software and chlorine of standard Iressa drug is replaced by bromide and

fluorine is removed from the structure . it is named as Iressa C . The figure also shows

the SMILES (simplified molecule input line entry specification) and general properties of

modified drug Iressa C.. molecular formula of modified drug Iressa C is C22 H25 Br N4 O3,

formula weight is 473.36, Nominal mass is 472 da, Avarae mass is 473.37 and surface

tension 56.8

Fig: 7. Structure of curcumin

 Fig 7 : shows the structure of natural Curcumin drug which is drawn in

chemsketch software and properties also calculated. Molecular formula of Curcumin is

C21 H24 O6, formula weight is 372.4, Nominal mass is 372 da, Avarae mass is 372.41 and

surface tension 49.6

Fig. 8: 3D structure of Curcumin

 Fig 8: shows the three-dimensional structure of curcumin. The 3D structure is converted

by online tool corina. The structure is visualized and labeled by rasmol molecular

visualization tool.

Fig : 9 . 3D structure of standard drug Iressa

 Fig 9 : shows the three-dimensional structure of Iressa The 3D structure is converted

by online tool corina. The structure is visualized and labeled by rasmol molecular

visualization tool.

Fig . 10: 3D structure of standard drug Iressa A

 Fig 10 : shows the three-dimensional structure of modified drug Iressa A The 3D

structure is converted by online tool corina. The structure is visualized and labeled by

rasmol molecular visualization tool.

Fig.11. 3D structure of standard drug Iressa B

 Fig 11 : shows the three-dimensional structure of modified drug Iressa B The 3D
structure is converted by online tool corina. The structure is visualized and labeled by
rasmol molecular visualization tool.
 Fig. 12: 3D structure of standard drug Iressa C

Fig12: shows the three-dimensional structure of modified drug Iressa C . The 3-D

structure is converted by online tool corina. The structure is visualized and labeled by

rasmol molecular visualization tool.

Epidermal growth factor receptor – standard drug Iressa complex

 Fig 13: Docking result of standard Iressa drug

Fig 13: shows the docked complex of the standard Iressa drug and Epidermal

growth factor recetpor . Figure12 also shows best frame is 100 and best docking score is

260.0
 Epidermal growth factor receptor – Iressa A complex

Fig 14 : Docking result of modified Iressa A drug

Figure 13. : Shows the docked complex of the modified drug Iressa A and

Epidermal growth factor receptor. In this best docking frame is 99 and best docking

score is 255.0
 Epidermal growth factor receptor – Iressa B complex

Fig 15 : Docking result of modified drug Iressa B

Figure 15. : Shows the docked complex of the modified drug Iressa A and

Epidermal growth factor receptor. In this best docking frame is 95 and best docking score

is 258.0
 Epidermal growth factor receptor – Iressa C complex

Fig 16 : Docking result of modified drug Iressa C

Figure 16 : Shows the docked complex of the modified drug Iressa C and
Epidermal growth factor receptor. In this best docking frame is 94 and best docking score
is 262.0
 Epidermal growth factor receptor – natural curcumin drug complex

Fig 17: Docking result of natural Curcumin drug

Figure 17 : shows the docked complex of the Curcumin drug and Epidermal growth

factor receptor. In this best docking frame is 99 and best docking score is 271.0
Energy Calculations

Since energy calculations involve contributions from every atom in the

system, the individual contributions of functional groups on the drug to drug-receptor

interactions or solvation energies can be estimated. This allows for a detailed understanding of

the relationship of structural changes to changes in binding to be determined.

Interaction energy of standard Iressa drug

Fig 18: Interaction energy of standard Iressa drug

100 models are generated after Docking Iressa to target

protein epidermal growth factor receptor and the best conformation is:-

Best Model: 100

Best docking Score: 260

 Interaction Energy Graph of Modified Drug Iressa A

Fig .19 :Interaction energy of modified drug Iressa A

100 models are generated after Docking modified Iressa A drug to target

protein epidermal growth factor receptor and the best conformation is:-

Best Model: 99

Best docking Score: 255

 Interaction Energy Graph of Modified Drug Iressa B

Fig 20 :Interaction energy of modified drug Iressa B

100 models are generated after Docking modified Iressa B drug to target

protein epidermal growth factor receptor and the best conformation is:-

Best Model: 95

Best docking Score: 258

 Interaction Energy Graph of Modified Drug Iressa C

Fig. 21.Interaction Energy Graph of Modified Drug Iressa C

100 models are generated after Docking modified Iressa C drug to target

protein epidermal growth factor receptor and the best conformation is:-

Best Model: 94

Best docking Score: 262

 Interaction Energy Graph of Natural Drug Curcumin

Fig 22. Interaction Energy Graph of Natural Drug Curcumin

100 models are generated after Docking natural curcumin drug to target

protein epidermal growth factor receptor and the best conformation is:-

Best Model: 99

Best docking Score: 271

 Docking score and interaction energy values comparison

Graph 1. Comparison of docking score and interaction energy values

This figure shows docking results and interaction energy values of drug receptor

complex. light blue color indicate docking score and the red color indicates interaction

energy value. from this graph curcumin epidermal growth factors receptors complex

having highest docking score and interaction energy values.there fore curcumin has the

potent to inhibit EGFR and prevent lung cancer.

 ADME PROPERTIES PREDICTION

Molecular weight comparison

Graph .2: Molecular weight comparison

Figure shows the molecular weight of natural drug curcumin , commercial durg

Iressa and modified iressa durgs. Molecular weight of curcumin is 372, iressa is 446.7,

iressa A is 491.2, Iressa B is 599.1 and Iressa C is 473.2. Based on the Lipinski 5 rule the

drug must have the molecular weight below 500. Curcumin has the lowest molecular

weight when compare to other durgs.

 Comparison of Hydrogen bond donors

Graph 3. Comparison of Hydrogen bond donors

This figure shows the number of hydrogen donors present in the selected drugs

curcumin and iressa. Curcumin has 2 H-donors , Iressa -1 , iressa A -1, Iressa B- 1 ,and

Iressa C-1. According to Lipinski rule of 5 the durg must have the hydrogen donors

below 5. So the curcumin drug passed Lipinski rule of 5.

 Comparison of hydrogen bond acceptors

Graph 4. Comparison of hydrogen bond acceptors

This figure shows the Hydrogen bond acceptors of curcumin , Iressa and Iressa

analogues. Curcumin has 6 hydrogen bond acceptors, Iressa has 7, Iressa A has 7, Iressa

B has 7, and Iressa C has 7. According to lipinski’s rule of 5 the drug should have the

number of H-bond acceptors below 12 . curcumin drug passed lipinski’s rule of 5.

 Comparison of Log P values (Partition coefficient)

Graph 5. Comparison of Log P values (Partition coefficient)

This figure shows the Log P values ( partition coefficient) of curcumin , Iressa ,

Iressa A, iressa B and iressa C. the log P value of curcumin is 2.64, Iressa is 3.18, Iressa

A is 3.36 and Iressa B is 4.26 and iressa C is 3.19. according to the lipinski’s rule the drug

which is having lowest log P value it will be a best drug . from this graph result

curcumin is the best inhibitor having the lowest partition coefficient value is 2.64.

ADME PROPERTIES COMPARSION

 Graph 6. Comparison of Log P values (Partition coefficient)

The above figure shows the comparison of Log p and H – donor and H- acceptor

values of the drugs. The blue color indicates hydrogen bond donors, pink color indicates

hydrogen bond acceptors and the light green color indicates Partition coefficient ( log P).

based on the lipinski’s rule of 5 the durg must have the hydrogen bond donors below 5

,hydrogen bond acceptors below 12 and partition coefficient( log P) value is below 5

.from the graph curcumin has the best result when compare to other durgs.

DOCKING RESULTS COMPARISON

 DOCKING INTERACTION
SL. NO. BEST FRAME SCORE ENERGY VALUE
COMPLEX

Epidermal growth factor receptor-

1. Curcumin 99 271 315

3. 100 260 289

Epidermal growth factor receptor -Iressa

4. Epidermal growth factor receptor - 99 255 308

Iressa A

5. Epidermal growth factor receptor - 95 258 296

Iressa B

6. Epidermal growth factor receptor - 94 262 303

Iressa C

Table 1. Comparison of docking results and interaction energy values

ADME Toxic values comparison

 Molecular Log p
Sl. No. Drug Name H-donor H-Acceptor
Weight

1. Curcumin 372 2 6 2.64

2. Iressa 446.7 1 7 3.18

3. Iressa A 491.2 1 7 3.36

4. Iressa B 599.1 1 7 4.26

5. Iressa C 473.2 1 7 3.19

Table 2. Comparison of ADME toxic values

Lipinski's Rule of Five states that, in general, an active drug has no more than one
violation of the following criteria:

• Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or
more hydrogen atoms)
• Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
• A molecular weight under 500 g/mol
• A partition coefficient log P less than 5

SUMMARY AND CONCLUSION

SUMMARY
 The target protein epidermal growth factor receptor (EGFR) is identified and

retrieved from Protein data Bank .The PDB id of the epidermal growth factor is 1MOX.

The Protein structure is visualized and active site amino acids are anylysed by RasMol

tool. The wire frame model structure of epidermal growth factor receptor (EGFR) is

shown in the (Figure 1).

Iressa and curcumin are important epidermal Growth factor receptor inhibitors

(EGFR). The structure of EGFR inhibitors has found in the pubchem compound database.

The 2D structure of curcumin and Iressa drug is retrieved from NCBI pubchem compund

database. The physiochemical parameters of these two inhibitors are analysed. Physio

chemical properties and the structural details of are shown in (Figure 2 and Figure 3).

By using chemsketch molecular drawing tool, we have done three modifications

in standard Iressa drug and they are named as Iressa A, Iressa B and Iressa C. In Iressa A

chlorin is replaced by bromin, in Iressa B flurin is replaced by iodine. Structural

modification and phsiochemical property details of all the drugs are shown in (Figure 4,

Figure 5 and Figure 6)

3 dimensional structure predictions of all the drugs have done in corina 3D

conversion tool. 3D structures of all the drugs are anlysed and visulalised in rasmol tool

then they are saved in pdb file format. 3D structural details of all the drugs are shown in

(Figure 8, Figure 9,Figure 10, Figure 11 and Figure 12).

Docking steps are done in VegaZZ software. Commercial drug Iressa is docked

with EGFR to form protein ligand complex, The docking score of Iressa with EGFR is

260 (Figure 13) and binding enery score of Iressa is 289 (Figure.18). All the modified

drugs are docked with its target protein Epideraml Growth Factor Receptor, docking
score and interaction energy values ae shown in (Figure, 14, Figure 15 and Figure 16).

The natural compound curcumin is docked with its target edpidermal growth factor

receptor. Docking score and interaction enery value is caluculated (Figure 17).

Inateraction energy calculation of all the five drugs is done in Escher NG

automatics docking system. Comparision of interaction energy value and docking score

of all the five drugs are shown in (Grpah 1)

Physiochemical properties of natural drug curcumin, commercial drug Iressa,

modified drugs Iressa A, Iressa B, and IressaC was predicted using ADME Boxes and

ADME Toxes Tools. Molecular weight of all the five drugs are predicted and values are

given in (Graph 2). Nurmber of Hydrogen bond donars and H bond acceptors are

calculated (Graph 3 and Graph 4). Partation coefficient value (Log P) of all the five drugs

are shown in (Graph 5).

Comparisons of all physio chemical properties of all the five drugs are shown in

(Graph 6). Based on the lipinski’s rule of 5 the durg must have the hydrogen bond donors

below 5, hydrogen bond acceptors below 12 and partition coefficient( log P) value is

below 5. From graphical result all the drugs are passed lipinski’s 5 rule.

Iressa and Curcumin inhibitors of Epidermal Growth factor receptors, which is

involved in the lung cancer. Of all the drugs present for lung cancer, It is opted
commercial drug Iressa which can be efficiently used for lung cancer And natural
Curcumin drug which can stop cancer its earliest stages, long before it’s detectable. We
therefore examined the effects of a selective EGFR tyrosine kinase inhibitor zd1839
(iressa) , on proliferation and survival of lung cancer cell lines by using docking software
tools(vega zz).Using chemskecth I have designed 3 new drug molecules (iressa A,iressa
B & Iressa C ) on the basis of iressa drug , and compared the commercial iressa drug
and natural curcumin drug by docking it on EGFR protein by using vega ZZ software .
on the basis of energy score I found that curcumin will be the best inhibitor than
comercial Iressa drug. The natural curcumin drug also passed the absorbtion,
distribution, metabolism and excretion (ADME) screening and Lipinski’s rule of 5. I
found that this natural curcumin drug will act as more efficient drug to inhibit EGFR
protein and stop signal transduction which is the major step in causing lung cancer . This
natural curcumin drug has the potential to be used for second generation of drug
development. It has to be proved in wet lab also. It can be used further in clinical trials to
test it effectiveness and for social benefit.
CONCULSIONS

The epidermal growth factor receptor (EGFR) has been reviewed. This protein is
involved in disease lung cancer and can consider as a successful drug target
Curcumin is the best inhibitor:-On comparing the interaction energy graph of all
inhibitors
1. Standard drug Iressa shows the score 260.0
2. Modified Iressa A drug shows score 255.0
3. Modified Iressa B drug shows the score 258.0
4. Modified Iressa C drug shows the score 262.0
5. Natural curcumin drug having best result score 271.0
6. Since highest the score best is the complex.
7. Since highest the score lower is the energy so according to energy graph and the
energy ranges it is concluded that curcumin is the best inhibitor having the
highest score of 271.0
Curcumin could be considered as a possible drug as it scores the
highest in the interaction energy graph.on comparing the ADME properties of
commercial drug iressa, modified drugs and natural curcumin drug ( by using
ADME tool ), I found that this natural curcumin is passed ADME screening and
lipinski rule of 5 .natural curcumin drug will act as more efficient drug to inhibit
EGFR protein and stop signal transduction which is the major step in causing lung
cancer.This natural curcumin drug has the potential to be used for second generation
of drug development. It has to be proved in wet lab also. It can be used further in
clinical trials to test it effectiveness and for social benefit.
 REFERENCES

Ademuyiwa FO, Hanna N, 2008, Cetuximab in non-small cell lung cancer.Expert Opin
Biol Ther.8(1):107-13.
Aggarwal B B, Kumar A, Aggarwal M S, Shishodia S. 2005, Curcumin derived from
turmeric (Curcuma longa): a spice for all seasons. In: Preuss H, ed. Phytopharmaceuticals
in Cancer Chemoprevention. Boca Raton: CRC Press;:349-387.

Aggarwal, B.B., Kumar, A. and Bharti, A. C., 2003, Anticancer potential of curcumin:
preclinical and clinical studies. Anticancer Res., 23, 363–398.

Aggarwal B B, Banerjee S, Bharadwaj U, Sung B, Shishodia S, Sethi G. 2007,Curcumin

induces the degradation of cyclin E expression through ubiquitin-dependent pathway and
up-regulates cyclin-dependent kinase inhibitors p21 and p27 in multiple human tumor
cell lines.Biochem Pharmacol. 1024-32.

Akrishnan, V. R. and Menon, V. P., 2001, Potential role of antioxidants during ethanol-
induced changes in the fatty acid composition and arachidonic acid metabolites in male
Wistar rats. Cell Biol. Toxicol., 17, 11–22.

Alvarez M, Roman E, Santos ES, Raez LE. 2007, New targets for non-small-cell lung
cancer therapy. Expert Rev Anticancer Ther. :1423-37.

Ammon, H. P. T. and Wahl, M. A., 1991, Pharmacology of Curcuma longa.Planta Med.,

57, 1–7
.
Ammon, H. P. T., Anazodo, M. I., Safayhi, H., Dhawan, B. N. and Srimal, R. C., 1992,
Curcumin: a potent inhibitor of leukotriene B4 formation in rat peritoneal
polymorphonuclear neutrophils (PMNL). Planta Med., 58, 26.

Anonymous. 1997. Antiproliferative effects of curcumin and (-)-epigallocatechin-3-

gallate (EGCG) on normal and premalignant human oral epithelial cells (Meeting
abstract). Proc Annu Meet Am Assoc Cancer Res 38:A1755

Antony S, et al. 1999. Immunomodulatory activity of curcumin. Immunol Invest 28:291-

303.

Anto RJ, et al. 2000. L-929 cells harboring ectopically expressed Rela resist curcumin-
induced apoptosis. J Biol Chem 275(21):15601-4.

Apisariyakul, A., Vanittanakomm N. and Buddhasukh, D., 1995, Antifungal activity of

turmeric oil extracted from Curcuma longa (Zingiberaceae). J. Ethnopharmacol., 49,
163–169.
Araujo, C. A. C. and Leon, L. L., 2001, Biological activities of Curcuma longa L. Mem.
Inst. Oswaldo Cruz, 96, 723–728.

Araujo, M. C., Dias, F. L. and Takahashi, C. S., 1999, Potentiation by turmeric and
curcumin of gamma-radiation-induced chromosome aberrations in Chinese hamster ovary
cells. Teratogen. Carcinogen.Mutagen, 19, 9–18.
Arbiser J L, Klauber N, Rohan R, et al. 1998, Curcumin is an in vivo inhibitor of
angiogenesis. Mol Med. ;4(6):376-383.

Arora, R. B., Basu, N., Kapoor, V. and Jain, A. P., 1971, Anti-inflammatory studies on
Curcuma longa (Turmeric). Indian J. Med. Res., 59, 1289–1295.

Arthurs C L, Wind N S, Whitehead R C, Stratford I J. 2007, Analogues of 2-

crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone (COTC) with anti-
tumor properties. Bioorg Med Chem Lett.:553-7.

Arun, N. and Nalini, N., 2002, Efficacy of turmeric on blood sugar and polyol pathway
in diabetic albino rats. Plant Foods Hum. Nutr., 57, 41–52.

Azuine, M. A. and Bhide, S. V., 1994, Adjuvant chemoprevention of experimental

cancer: catechin and dietary turmeric in forestomach and oral cancer models. J.
Ethnopharmacol., 44, 211–217.

Azuma I, Saiki I. 1994, Prevention of cancer metastasis in mice with fibronectin-related

substances. Princess Takamatsu Symp.;24:125-41

Bachmeier B, Nerlich A G, Iancu C M, Cilli M, Schleicher E, Vené R, Dell'Eva R,

Jochum M, Albini A, Pfeffer U. 2007,The chemopreventive polyphenol Curcumin
prevents hematogenous breast cancer metastases in immunodeficient mice.
Cell Physiol Biochem:137-52.

Baguley BC, Finlay GJ. 1988, Derivatives of amsacrine: determinants required for high
activity against Lewis lung carcinoma.J Natl Cancer Inst.:195-9.

Began, G., Sudharshan, E., Udaya Shankar, K. and Appu Rao, A. G., 1999, Interaction of
curcumin with phosphatidylcholine: a spectrofluorometric study. J. Agric. Food Chem.,
47, 4992–4997.

Baird WM, Hooven LA, Mahadevan B. 2005 Carcinogenic polycyclic aromatic

hydrocarbon-DNA adducts and mechanism of action. Environ Mol Mutagen.;45(2-
3):106-114.

Balcerek M, Matławska I. 2005, [Preventive role of curcumin in lung cancer]

Przegl Lek.;62(10):1180-1.

Bandyopadhyay, U., Das, D. and Banerjee, R. K., 1999,Reactive oxygen species:

oxidative damage and pathogenesis. Curr Sci., 77, 658–666.
Banerjee, A. and Nigam, S. S., 1978, Antimicrobial efficacy of the essential oil of
Curcuma longa. Indian J. Med. Res., 68, 864–866.

Banerji A, Chakrabarti J, Mitra A, Chatterjee A. 2004, Effect of Curcumin on gelatinase

A (MMP-2) activity in B16F10 melanoma cells. Cancer Lett.;211(2):235-242.
 Bano G, Raina R K, Zutshi U, Bedi K L, Johri R K, Sharma S C. 1991, Effect of
piperine on bioavailability and pharmacokinetics of propranolol and theophylline in
healthy volunteers. Eur J Clin Pharmacol.;41(6):615-617.

Bareschino M A, Schettino C, Troiani T, Martinelli E, Morgillo F, Ciardiello F.

2007,Erlotinib in cancer treatment. Ann Oncol. 18 Suppl 6:vi35-41

Benenson Y, Gil B, Ben-Dor U, Adar R, Shapiro E. 2004, An autonomous molecular

computer for logical control of gene expression.Nature.:423-9.

Bröker LE, Giaccone G. 2002, The role of new agents in the treatment of non-small cell
lung cancer. Eur J Cancer. 38(18):2347-61.

Bild A H, 2006, Oncogenic pathway signatures in human cancers as a guide to targeted

therapies. Nature.:353-7.

Bhatia, A., Singh, G. B. and Khanna, N. M., Effect of curcumin, 1964, its alkali salts and
Curcuma longa oil in histamine induced gastric ulceration.Indian J. Exp. Biol., 2, 158–
160.

Bhaumik, S., Jyothi, M. D. and Khar, A., 2000, Differential modulation of nitric oxide
production by curcumin in host macrophages and NK cells. FEBS Lett., 483, 78–82.

Bhavani Shankar, T. N. and Sreenivasa Murthy, V., 1979, Effect of turmeric(Curcuma

longa) fractions on the growth of some intestinaland pathogenic bacteria in vitro. Indian
J. Exp. Biol., 17, 1363–1366.

Bhavani Shankar, T. N., Shantha, N. V., Ramesh, H. P., Murthy,I. A. S. and Murthy, V. S.,
1980, Toxicity studies on turmeric (Curcuma longa): acute toxicity studies in rats, guinea
pigs and monkeys. Indian J. Exp. Biol., , 18, 73–75.

Bierhous, A. et al., 1997, The dietary pigment curcumin reduces endothelial tissue factor
gene expression by inhibiting binding of AP-1 to the DNA and activation of NFkB.
Thromb. Haematostasis, 77, 772–782.

Blasiak, J., Trzeciak, A., Malecka-Panas, E., Drzewoski, J., Iwamienko,T., Szumiel, . and
Wojewodzka, M., 1999, DNA damage and repair in human lymphocytes and gastric
mucosa cells exposed to chromium and curcumin. Teratogen. Carcinogen. Mutagen,
19,19–31.

Bonham L, Leung D W, White T, Hollenback D, Klein P, Tulinsky J, Coon M, de Vries P,

Singer J W. 2003, Lysophosphatidic acid acyltransferase-beta: a novel target for induction
of tumour cell apoptosis. Expert Opin Ther Targets.:643-61.
Brouet I, Ohshima H. Curcumin, 1995, an anti-tumour promoter and anti-inflammatory
agent, inhibits induction of nitric oxide synthase in activated macrophages. Biochem
Biophys Res Commun.;206(2):533-540.

Buolamwini J K. 2000, Cell cycle molecular targets in novel anticancer drug discovery.
Curr Pharm Des. Mar;6(4):379-92.

Byeon S R, Lee J H, Sohn J H, Kim D C, Shin K J, Yoo K H, Mook-Jung I, Lee W K,

Kim D J. 2007, Bis-styrylpyridine and bis-styrylbenzene derivatives as inhibitors for
Abeta fibril formation. Bioorg Med Chem Lett. 1466-70.

Caltagirone S, Rossi C, Poggi A, Ranelletti F O, Natali P G, Brunetti M, Aiello

FBPiantelli M. 2000,Flavonoids apigenin and quercetin inhibit melanoma growth and
metastatic potential.Int J Cancer: 595-600.

Chainani-Wu, N., 2003, Safety and antiinflammatory activity of curcumin:a component

of turmeric (Curcuma longa). J. Altern. Complement Med., 9, 161–168.

Chandra, D. and Gupta, S. S., 1972, Antiinflammatory and antiarthritic activity of volatile
oil of Curcuma longa (Haldi). Indian J. Med.Res., 60, 138–142.

Chen, H. W. and Huang, H. C., 1998, Effect of curcumin on cell cycle progression and
apoptosis in vascular smooth cells. Br. J. Pharmacol., 124, 1029–1040.

Chen, Y-C., Kuo, T-C., Lin-Shiau, S-Y. and Lin, J-K., 1996, Induction of HSP70 gene
expression by modulation of Ca2+ ion and cellular P53 protein by curcumin in colorectal
carcinoma cells. Mol. Carcinogenesis, 17, 224–234.

Cheng A L, Hsu C H, Lin J K, et al. 2001, Phase I clinical trial of curcumin, a

chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer
Res.;21(4B):2895-2900.

Chey, W. Y., Millikan, L., Lee, K. Y., Watanabe, S., Shiratori, K.and Takeuchi, T., 1983,
Effect of 1-phenylpentanol on release of secretin and exocrine pancreatic secretion in
dogs and humans. Gastroenterology, 84, 1578–1584.

Choudhuri, T., Pal, S., Aggarwal, M. L., Das, T. and Sa, G., 2002, Curcumin induces
apoptosis in human breast cancer cells through p53-dependent Bax induction. FEBS
Lett., 512, 334–340.

Chow LQ, Eckhardt SG. 2007, Sunitinib: from rational design to clinical efficacy. J Clin
Oncol. 884-96.

Chuang S E, Kuo ML, Hsu C H, et al. 2000; Curcumin-containing diet inhibits

diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis. 21(2):331-
335.
Ciardiello F, Tortora G.2008, EGFR antagonists in cancer treatment. N Engl J Med.
13;358(11):1160-74.

Ciolino H P, Daschner PJ, Wang T T, Yeh G C. 1998, Effect of curcumin on the aryl
hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma
cells. Biochem Pharmacol.;56(2):197-206.

Cipriani, B. et al., 2001, Curcumin inhibits activation of Vg9Vd2 T cells by

phosphoantigens and induces apoptosis involving apoptosis inducing factor and large
scale DNA fragmentation. J. Immunol., 167, 3454–3462.

Cole G M, Morihara T, Lim G P, Yang F, Begum A, Frautschy S A .2004, NSAID and

Antioxidant Prevention of Alzheimer's Disease: Lessons from In Vitro and Animal
Models. Ann N Y Acad Sci.;1035:68-84.

Comis R L, Friedland D M. 1995, New chemotherapy agents in the treatment of

advanced non-small cell lung cancer: an update including data from the Seventh World
Conference on Lung Cancer. Lung Cancer:S63-99.

Cream, G. P., Shearman, D. J. C. and Small, W. P., 1974, Diseases of the digestive
system. In Davidsons Principles and Practice of Medicine (ed. Macleod, J.) The English
Language Book Society and Churchill Livingstone, Edinburgh, 11th edn, p. 456.

Chang A Y. 2008, The role of gefitinib in the management of Asian patients with non-
small cell lung cancer. Expert Opin Investig Drugs,17(3):401-11

Chlordane found in foods decades after pesticide use. Press release of the American
Chemical Society, May 2, 2000.

Chuang S E, et al. 2000. Curcumin-containing diet inhibits diethylnitrosamine-induced

murine hepatocarcinogenesis. Carcinogenesis 21:331-35..

Churchill M, et al. 2000. Inhibition of intestinal tumors by curcumin is associated with

changes in the intestinal immune cell profile. J Surg Res 89:169-75

Ciolino H P, et al. 1998. Effect of curcumin on the aryl hydrocarbon receptor and
cytochrome p450 1A1 in MCF-7 human breast carcinoma cells. Biochem Pharmacol
56:197-06.

Dasgupta, S. R., Sinha, M., Sahana, C. C. and Mukherjee, B. P., 1969, A study of the
effect of an extract of Curcuma longa Linn. on experimental gastric ulcers in animals.
Indian J. Pharmacol., 1, 49–54.
Davies A M, Gandara D R, Lara P N Jr, Mack P C, Lau D H, Gumerlock P H. 2003,
Antisense oligonucleotides in the treatment of non-small-cell lung cancer. Clin Lung
Cancer. :S68-73.

De Clercq, E., 2000, Current lead natural products for the chemotherapy of human
immunodeficiency virus (HIV) infection. Med. Res. Rev., 20, 323–349.

Dean B, Oguchi H, Cai S, Otsuji E, Tashiro K, Hakomori S, Toyokuni T. 1993, Synthesis

of multivalent beta-lactosyl clusters as potential tumor metastasis inhibitors. Carbohydr
Res:175-92.

Dediu M, Median D, Alexandru A, Vremes G, Gal C. 2007, Tyrosine kinase inhibitors in

non-small cell lung and pancreatic cancer: the emerging role of erlotinib.

Deeb, D., Xu, Y. X., Jiang, H., Gao, X., Janakiram, N., Chapman,R. A. and Gautam, S.
C., 2003, Curcumin (diferuloyl-methane) enhances tumor necrosis factor-related
apoptosis-inducing ligand-induced apoptosis in LNCaP prostate cancer cells. Mol. Cancer
Ther., 2, 95–103.

Deodhar S D, Sethi R, Srimal R C. 1980, Preliminary study on antirheumatic activity of

curcumin (diferuloyl methane). Indian J Med Res.;71:632-634.

Dhar, M. L., Dhar, M. M., Dhawan, B. N., Mehrotra, B. N. and Ray,C., 1968, Screening
of Indian plants for biological activity: I. Indian J. Exp. Biol., 6, 232–247.

Dickinson D A, Iles KE, Zhang H, Blank V, Forman H J. 2003, Curcumin alters EpRE
and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression.
Faseb J.;17(3):473-475.

Dickinson D A, Levonen AL, Moellering D R, et al. 2004, Human glutamate cysteine

ligase gene regulation through the electrophile response element. Free Radic Biol
Med.;37(8):1152-1159.

Di Santo R, Costi R, Artico M, Ragno R, Greco G, Novellino E, Marchand C, Pommier

Y. 2005, Design, synthesis and biological evaluation of heteroaryl diketohexenoic and
diketobutanoic acids as HIV-1 integrase inhibitors endowed with antiretroviral activity.
Farmaco.:409-17.

Ding Q, Jia G, Lown J W. 2000,Synthesis and antitumor cytotoxicity evaluation of

pyrido[4,3,2-de]quinolines and isoquinolino[6,5,4,3-cde]quinolines. Anticancer Drug
Des. :99-108.

Dixit, V. P., Jain, P. and Joshi, S. C., 1988, Hypolipidaemic effects of Curcuma longa L
and Nardostachys jatamansi DC in triton-induced hyperlipidaemic rats. Indian J. Physiol.
Pharmacol., 32,299–304.
Du A, Zhao B, Yin D, Zhang S, Miao J. 2006, Safrole oxide induces apoptosis by
activating caspase-3, -8, and -9 in A549 human lung cancer cells. Bioorg Med Chem
Lett.:81-3.

Duvoix A, Blasius R, Delhalle S, et al. 2005Chemopreventive and therapeutic effects of

curcumin. Cancer Lett.;223(2):181-190.

Duvoix, A. et al., 2003, Induction of apoptosis by curcumin: mediation by glutathione S-

transferase P1-1 inhibition. Biochem. Pharmacol., 66, 1475–1483.

Eberhard D A, Giaccone G, Johnson B E; 2008, Non-Small-Cell Lung Cancer Working

Group.Biomarkers of response to epidermal growth factor receptor inhibitors in Non-
Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial
setting. J Clin Oncol. 20;26(6):983-94

Egan M E, Pearson M, Weiner S A, et al. 2004, Curcumin, a major constituent of

turmeric, corrects cystic fibrosis defects. Science.;304(5670):600-602.

Eigner, D. and Scholz, D., 1990, Das Zauberbuchlein der Gyani Dolma. Pharm. Unserer
Zeit, 19, 141–152.

Eigner, D. and Scholz, D., 1999, Ferula asa-foetida and Curcuma longa in traditional
medicinal treatment and diet in Nepal. J. Ethnopharmacol., 67, 1–6.

Elattar T M, et al. 2000. The inhibitory effect of curcumin, genistein, quercetin and
cisplatin on the growth of oral cancer cells in vitro. Anticancer Res 20(3A):1733-38.

Feigal E G, Christian M, Cheson B, Grever M, Friedman M A. 1993, New

chemotherapeutic agents in non-small-cell lung cancer.
Semin Oncol. (2):185-201.

Ferreira, L. A. F., Henriques, O. B., Andreoni, A. A. S., Vital, G. R. F.,Campos, M. M. C.,

Habermehl, G. G. and Moraes, V. L. G., 1992, Antivenom and biological effects of ar-
turmerone isolated from Curcuma longa (Zingiberaceae). Toxicon, 30, 1211–1218.

Felip E, Santarpia M, Rosell R. 2007, Emerging drugs for non-small-cell lung cancer.
Expert Opin Emerg Drugs. 449-60.
Fikes J D, Sette A. 2003,Design of multi-epitope, analogue-based cancer vaccines.
Expert Opin Biol Ther. :985-93.

Frankel, E. N., Lipid Oxidation, The Oily Press, Dundee, Scotland, 1998, pp. 129–160.

Frank N, Knauft J, Amelung F, Nair J, Wesch H, Bartsch H. 2003, No prevention of liver

and kidney tumors in Long-Evans Cinnamon rats by dietary curcumin, but inhibition at
other sites and of metastases. Mutat Res;523-524:127-35.
Frautschy S A, Hu W, Kim P, et al. Phenolic anti-inflammatory antioxidant reversal of
Abeta-induced cognitive deficits and neuropathology. Neurobiol Aging. 2001;22(6):993-
1005.

Füllbeck M, Huang X, Dumdey R, Frommel C, Dubiel W, Preissner R. 2005, Novel

curcumin- and emodin-related compounds identified by in silico 2D/3D conformer
screening induce apoptosis in tumor cells. BMC Cancer.;5:97.

Galati, G., Sabzevari, O., Wilson, J. X. and O’Brien, P. J., 2002, Prooxidant activity and
cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics.
Toxicology, 177, 91–104.

Gandy S. 2005, The role of cerebral amyloid beta accumulation in common forms of
Alzheimer disease. J Clin Invest. 115(5):1121-1129.

Garcea G, Berry D P, Jones D J, et al. 2005,Consumption of the putative

chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the
colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers
Prev. 14(1):120-125.

Garcea G, Jones D J, Singh R, et al. 2004 Detection of curcumin and its metabolites in
hepatic tissue and portal blood of patients following oral administration. Br J
Cancer.;90(5):1011-1015.

Garg, S. K., 1974, Effect of Curcuma longa (rhizomes) on fertility in experimental

animals. Planta Med., 26, 225–227.

Garg, S. K., Mathur V. S. and Chaudhury, R. R., 1978, Screening of Indian plants for
antifertility activity. Indian J. Exp. Biol., 16, 1077–1079.

Gautam, S. C., Xu, Y. X., Pindolia, K. R., Janakiraman, N. and Chapman, R. A., 1998,
Nonselective inhibition of proliferation of transformed and nontransformed cells by the
anticancer agent carcumin (diferuloylmethane). Biochem. Pharmacol., 55, 1333–1337.

Gescher A J, Sharma RA, Steward W P. 2001, Cancer chemoprevention by dietary

constituents: a tale of failure and promise. Lancet Oncol. 371-9.

Giaccone G. 2002, Targeted therapy in non-small cell lung cancer. Lung Cancer. Nov;38
Suppl 2:S29-32.

Ghatak, N. and Basu, N., 1972, Sodium curcuminate as an effective antiinflammatory

agent. Indian J. Exp. Biol., 10, 235–236.

Goel, A., Boland, C. R. and Chauhan, D. P., 2001, Specific inhibition of

cyclooxygenase-2(COX-2) expression by dietary Curcumin in HT-29 human colon
cancer cells. Cancer Lett., 172, 111–118.
Gomes Dde, C., Alegrio, L. V., de Lima, M. E., Leon L. L. and Araujo, C. A., 2002,
Synthetic derivatives of Curcumin and their activity against Leishmania amazonensis.
Arzneimittelforschung, 52, 120–124.

Guo F, Das S, Mueller B M, Barbas C F 3rd, Lerner R A, Sinha S C. 2006, Breaking the
one antibody-one target axiom.Proc Natl Acad Sci U S A.:11009-14.

Gridelli C, Rossi A, Maione P. 2003, Treatment of non-small-cell lung cancer: state of the
art and development of new biologic agents.Oncogene. :6629-38.

Grünwald V, Hidalgo M. 2003, Development of the epidermal growth factor receptor

inhibitor Tarceva (OSI-774). Adv Exp Med Biol.;532:235-46

Gridelli C, Maione P, Rossi A, De Marinis F. 2007, The role of bevacizumab in the

treatment of non-small cell lung cancer: current indications and future
developments.Oncologist.12(10):1183-93.

Gridelli C, Rossi A, Maione P, Colantuoni G, Del Gaizo F, Ferrara C, Nicolella D,

Guerriero C. 2007, Erlotinib in non-small-cell lung cancer. Expert Opin Pharmacother.
Oct;8(15):2579-92

Gujral, M. L., Chowdhury, N. K. and Saxena, P. N., 1953, The effect of certain
indigenous remedies on the healing of wounds and ulcers. J. Indian State Med. Assoc.,
22, 273–276.

Gupta, B., Kulshrestha, V. K., Srivastava, R. K. and Prasad, D. 1980, N.,Mechanisms of

curcumin induced gastric ulcer in rats. Indian J. Med.Res., 71, 806–814.

Gong Y, Somwar R, Politi K, Balak M, Chmielecki J, Jiang X, Pao W, 2007, nduction of

BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-
dependent lung adenocarcinomas. LoS Med. 9;4(10):e294.

Guddneppanavar R, Saluta G, Kucera G L, Bierbach U. 2006, Synthesis, biological

activity, and DNA-damage profile of platinum-threading intercalator conjugates designed
to target adenine. J Med Chem. 3204-14.

Hakimelahi G H, Shia K S, Pasdar M, Hakimelahi S, Khalafi-Nezhad A, Soltani M N,

Mei N W, Mei H C, Saboury A A, Rezaei-Tavirani M, Moosavi-Movahedi AA. 2002,
Design, synthesis, and biological evaluation of a cephalosporin-monohydroguaiaretic
acid prodrug activated by a monoclonal antibody-beta-lactamase conjugate.
Bioorg Med Chem. :2927-32.

Halliwell, B. and Gutteridge, J. M. C., 1990, Role of free radicals and catalytic metal ions
in human disease: an overview. Methods Enzymol., 186, 1–85.
Halliwell, B., 1998, In Oxidative Stress in Skeletal Muscle (eds Reznick,A. Z. et al.),
Birkhauser, Verlag Basel, Switzerland, pp. 1–27.

Hanif, R., Qiao, L., Shiff, S. J. and Rigas, B., 1997, Curcumin, a natural plant phenolic
food additive, inhibits cell proliferation and induces cell cycle changes in colon
adenocarcinoma cell lines by a prostaglandin independent pathway. J. Lab. Clin. Med.,
130, 576–584.

Heath D D, Khwaja F, Rock C L. 2004 Curcumin content of turmeric and curry powders.
FASEB J.;18(4):A125.

Hecht S S, Kenney P M, Wang M, Trushin N, Agarwal S, Rao AV, Upadhyaya P. 1999,

Evaluation of butylated hydroxyanisole, myo-inositol, curcumin, esculetin, resveratrol
and lycopene as inhibitors of benzo[a]pyrene plus 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone-induced lung tumorigenesis in A/J mice.
Cancer Lett. 123-30.

Heery D M, Fischer P M. 2007, Pharmacological targeting of lysine acetyltransferases in

human disease: a progress report. Drug Discov Today. 88-99.

He L, Chang H X, Chou T C, Savaraj N, Cheng C C. 2003 Design of antineoplastic

agents based on the '2-phenylnaphthalene-type' structural pattern--synthesis and
biological activity studies of 11H-indolo[3.2-c]quinoline derivatives.
Eur J Med Chem. :101-7.

Hergenhahn, M., Soto, U., Weninger, A., Polack, A., Hsu, C. H.,Cheng, A. L. and Rosl,
F., 2002, The chemopreventive compound curcumin is an efficient inhibitor of Epstein-
Barr virus BLZF1 transcription in Raji DR-LUC cells. Mol. Carcinogen., 33, 137–145.

Hikino, H., 1985, Antihepatotoxic activity of crude drugs. Yakugaku Zasshi, 105, 109–
118.

Holder, G. M., Plummer, J. L. and Ryan, A. J., 1978, The metabolism and excretion of
curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) in the rat.
Xenobiotica, 8, 761–768.

Hong J, Bose M, Ju J, et al, 2004. Modulation of arachidonic acid metabolism by

curcumin and related beta-diketone derivatives: effects on cytosolic phospholipase A(2),
cyclooxygenases and 5-lipoxygenase. Carcinogenesis.;25(9):1671-1679.

Huang M T, Lou Y R, Ma W, Newmark H L, Reuhl K R, Conney A H. 1994, Inhibitory

effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice.
Cancer Res.;54(22):5841-5847.
Huang M T, Lou Y R, Xie J G, et al. 1998 Effect of dietary curcumin and
dibenzoylmethane on formation of 7,12-dimethylbenz[a]anthracene-induced mammary
tumors and lymphomas/leukemias in Sencar mice. Carcinogenesis.;19(9):1697-1700.

Huang, M. T., Smart, R. C., Wong, Ch. Q. and Conney, A. H., 1988, Inhibitory effect of
curcumin, chlorogenic acid, caffeic acid, and ferulic acid on tumor promotion in mouse
skin by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res., 48, 5941–5946.

Huang CL, Yokomise H, Fukushima M, Kinoshita M. 2006, Tailor-made chemotherapy

for non-small cell lung cancer patients. Future Oncol. 289-99.

Ichiki K, Mitani N, Doki Y, Hara H, Misaki T, Saiki I. 2000, Regulation of activator

protein-1 activity in the mediastinal lymph node metastasis of lung cancer.Clin Exp
Metastasis.; 539-45

Ikezaki S, Nishikawa A, Furukawa F, et al. 2001 Chemopreventive effects of Curcumin

on glandular stomach carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine
and sodium chloride in rats. Anticancer Res.;21(5):3407-3411.

Italiano A, Vandenbos F B, Otto J, Mouroux J, Fontaine D, Marcy P Y, Cardot N, Thyss

A, Pedeutour F. 2006, Comparison of the epidermal growth factor receptor gene and
protein in primary non-small-cell-lung cancer and metastatic sites: implications for
treatment with EGFR-inhibitors.

Iqbal M, Sharma S D, Okazaki Y, Fujisawa M, Okada S. 2003, Dietary supplementation

of curcumin enhances antioxidant and phase II metabolizing enzymes in ddY male mice:
possible role in protection against chemical carcinogenesis and toxicity. Pharmacol
Toxicol.;92(1):33-38.

Ireson C, Orr S, Jones D J, et al. 2001, Characterization of metabolites of the

chemopreventive agent curcumin in human and rat hepatocytes and in the rat in vivo, and
evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2 production.
Cancer Res.;61(3):1058-1064.

Ireson C R, Jones D J, Orr S, et al. 2002, Metabolism of the cancer chemopreventive

agent curcumin in human and rat intestine. Cancer Epidemiol Biomarkers
Prev.;11(1):105-111.

Inoue K. 2002 [Drug delivery systems for cancer chemotherapy] Nippon Geka Gakkai
Zasshi. Feb;103(2):224-8.

Jain, J. P., Bhatnagar, L. S. and Parsai, M. R., J. Res. 1979, Indian Med. Yoga
Homeopathy, 14, 110.

Jain, S. K. and DeFillips, R. A., 1991 Medicinal Plants of India, 1991,Reference

Publications, Algonac, Michigan, p. 120.
Jana, N. R., Dikshit, P., Goswami, A. and Nukina, N., 2004, Inhibition of proteasomal
function by curcumin induces apoptosis through mitochondrial pathway. J. Biol. Chem.,
279, 11680–11685.

Jaruga, E., Bielak-Zmijewska, A., Sikora, E., Skierski, J., Radziszewska, E., Piowcka, K.
and Bartosz, G., 1998,Glutathione-independent mechanism of apoptosis inhibition by
curcumin in rat thymocytes.Biochem. Pharmacol., 56, 961–965.

Jia Z, Zhang H, Huang J. 2003, Synthesis of poly(ethylene glycol) with sulfadiazine and
chlorambucil end groups and investigation of its antitumor activity. Bioorg Med Chem
Lett. :2531-4.

Jayaprakasha, G. K., Negi, P. S., Anandharamakrishnan, C. and Sakariah, K. K. 2001,,

Chemical composition of turmeric oil – a byproduct from turmeric oleorsin industry and
its inhibitory activity against different fungi. Z. Naturforsch., C, 56, 40–44.

Jentzsch, K., Gonda, T. and Holler, H., 1959, Paper chromatographic and
pharmacological investigations on Curcuma pigments. Pharm. Acta Helv.,34, 181–188.

Joe B, Vijaykumar M, Lokesh B R. 2004, Biological properties of curcumin-cellular and

molecular mechanisms of action. Crit Rev Food Sci Nutr.;44(2):97-111.

Joe, B. and Lokesh, B. R., 1994, Role of capsaicin, curcumin and dietary n-3 fatty acids
in lowering the generation of reactive oxygen species in rat peritoneal macrophages.
Biochim. Biophys. Acta,1224, 255–263.

Kachadourian R, Day BJ. 2006, Flavonoid-induced glutathione depletion: potential

implications for cancer treatment. Free Radic Biol Med.: 65-76.

Kalpana C, Rajasekharan KN, Menon VP. 2005, Modulatory effects of curcumin and
curcumin analog on circulatory lipid profiles during nicotine-induced toxicity in Wistar
rats.

Kamal-Eldin, A., Frank, J., Razdan, A., Tengblad, S., Basu, S. and Vessby, B., 2000,
Effects of dietary phenolic compounds on tocopherol, cholesterol, and fatty acids in rats.
Lipids, 35, 427–435.

Kang, H. C. et al., 2002, Curcumin inhibits collagen synthesis and hepatic stellate cell
activation in vivo and in vitro. J. Pharm. Pharmacol., 54, 119–126.

Kapoor, L. D., 1990, Hand book of Ayurvedic Medicinal Plants, CRC Press, Boca Raton,
Florida, p. 185.

Karunagaran D, Rashmi R, Kumar T R. 2005, Induction of apoptosis by curcumin and its

implications for cancer therapy. Curr Cancer Drug Targets.;5(2):117-129.
Karamouzis M V, Konstantinopoulos P A, Papavassiliou A G. 2007, The role of STATs in
lung carcinogenesis: an emerging target for novel therapeutics.
J Mol Med. May; 85(5): 427-36.

Kato, K, Ito, H., Kamei, K. and Iwamoto, I., 1998, Stimulation of the stress-induced
expression of stress proteins by curcumin in cultured cells and in rat tissues in vivo. Cell
Stress Chaperones, 3, 152–160.

Kawamori T, Lubet R, Steele V E, et al. 1999, Chemopreventive effect of curcumin, a

naturally occurring anti-inflammatory agent, during the promotion/progression stages of
colon cancer. Cancer Res.;59(3):597-601.

Kawabe S, Nishikawa T, Munshi A, Roth JA, Chada S, Meyn R E. 2002, Adenovirus-

mediated mda-7 gene expression radiosensitizes non-small cell lung cancer cells via
TP53-independent mechanisms. Mol Ther. 637-44.

Kelly, M. R., Xu, J., Alexander, K. E. and Loo, G., 2001,Disparate effects of similar
phenolic phytochemicals as inhibitors of oxidative damage to cellular DNA. Mutat. Res.,
, 485, 309–318.

Kelland L R. 2004, of mice and men: values and liabilities of the athymic nude mouse
model in anticancer drug development. Eur J Cancer. :827-36.

Khar, A., Ali, A. M., Pardhasaradhi, B. V., Begum, Z. and Anjum, R., 1999, Antitumor
activity of curcumin is mediated through the induction of apoptosis in AK-5 tumor cells.
FEBS Lett., 445, 165–168.

Khar, A., Ali, A. M., Pardhasaradhi, B. V., Varalakshmi, C. H., Anjum, R. and Kumari, A.
L., 2001, Induction of stress response renders human tumor cell lines resistant to
curcumin mediated apoptosis: role of reactive oxygen intermediates. Cell Stress
Chaperones, 6, 368–376.

Kiso, Y., Suzuki, Y., Watanabe, N., Oshima, Y. and Hikino, H., 1983,Antihepatotoxic
principles of Curcuma longa rhizomes. Planta Med., 49, 185–187.

Koide, T., Nose, M., Ogihara, Y., Yabu, Y. and Ohta, N., 2002, Leishmanicidal effect of
curcumin in vitro. Biol. Pharm. Bull., 25,131–133.

Kosuge, T., Ishida, H. and Yamazaki, H., 1985, Studies on active substances in the herbs
used for oketsu (‘stagnant blood’) in Chinese medicine. III. On the anticoagulative
principles in Curcumae rhizoma.Chem. Pharm. Bull. (Tokyo), 33, 1499–1502.

Kolokythas G, Kostakis IK, Pouli N, Marakos P, Skaltsounis AL, Pratsinis H. 2002,

Design and synthesis of some new pyranoxanthenone aminoderivatives with cytotoxic
activity. Bioorg Med Chem Lett. :1443-6.
Krishnaswamy K, Goud V K, Sesikeran B, Mukundan M A, Krishna T P. 1998,
Retardation of experimental tumorigenesis and reduction in DNA adducts by turmeric
and curcumin. Nutr Cancer.;30(2):163-166.

Kwon H J. 2006, Discovery of new small molecules and targets towards angiogenesis via
chemical genomics approach. Curr Drug Targets.:397-405.

Kumar, S., Narain, U., Tripathi, S. and Misra, K., 2001, Synthesis of curcumin
bioconjugates and study of their antibacterial activities against beta-lactamase-producing
microorganisms. Bioconjug. Chem., 12, 464–469.

Kumar, V., Lewis, S. A., Mutalik, S., Shenoy, D. B., Venkatesh and Udupa, N. 2002,,
Biodegradable microspheres of curcumin for treatment of inflammation. Indian J.
Physiol. Pharmacol., 46, 209–217.

Kumar S, Dubey K K, Tripathi S, Fujii M, Misra K. 2000, Design and synthesis of

curcumin-bioconjugates to improve systemic delivery.
Nucleic Acids Symp Ser.;(44):75-6.

Kuo, M. L., Huang, T. S. and Lin, J. K., 1317, Curcumin, an antioxidant and anti-tumor
promoter, induces apoptosis in human leukemia cells.Biochim. Biophys. Acta, 1996, 95–
100.

Kuttan, R., Bhanumathy, P., Nirmala, K. and George, M. C., 1985, Potential anticancer
activity of turmeric (Curcuma longa). Cancer Lett., 29, 197–202.

Kuz'min V E, Artemenko A G, Lozytska R N, Fedtchouk A S, Lozitsky V P, Muratov E

N, Mescheriakov A K. 2005, Investigation of anticancer activity of macrocyclic Schiff
bases by means of 4D-QSAR based on simplex representation of molecular structure.
SAR QSAR Environ Res:219-30.

Lal B, Kapoor A K, Agrawal P K, Asthana OP, Srimal R C. 2000, Role of curcumin in

idiopathic inflammatory orbital pseudotumours. Phytother Res. 14(6):443-447.

Lal B, Kapoor A K, Asthana O P, et al. 1999, Efficacy of curcumin in the management of

chronic anterior uveitis. Phytother Res.;13(4):318-322.

Lampe JW, Peterson S. Brassica, 2002, biotransformation and cancer risk: genetic
polymorphisms alter the preventive effects of cruciferous vegetables. J Nutr.;132(10)

Lee J, Jung H H, Im Y H, Kim J H, Park JO, Kim K, Kim W S, Ahn J S, Jung C W, Park
Y S, Kang W K, Park K. 2006, Interferon-alpha resistance can be reversed by inhibition
of IFN-alpha-induced COX-2 expression potentially via STAT1 activation in A549 cells.
Oncol Rep. 1541-9.
Le Querrec A, Duval D, Tobelem G. 1993, Tumour angiogenesis. Baillieres Clin
Haematol. Sep;6(3):711-30.

Lev-Ari S, Starr A, Vexler A, Karaush V, Loew V, Greif J, Fenig E, Aderka D, Ben-Yosef

R. 2006, Inhibition of pancreatic and lung adenocarcinoma cell survival by curcumin is
associated with increased apoptosis, down-regulation of COX-2 and EGFR and inhibition
of Erk1/2 activity.Anticancer Res:4423-30.

Lechtenberg M, Quandt B, Nahrstedt A. 2004, Quantitative determination of

curcuminoids in Curcuma rhizomes and rapid differentiation of Curcuma domestica Val.
and Curcuma xanthorrhiza Roxb. by capillary electrophoresis. Phytochem
Anal.;15(3):152-158.

Lee, C. J., Lee, J. H., Seok, J. H., Hur, G. M., Park, Y. C., Seol, I. C. and Kim, Y. H. 2003,
Effects of baicalein, berberine, curcumin and hespiridin on mucin release from airway
goblet cells. Planta Med., 69, 523–526.

Levitzki A. 2003, Protein kinase inhibitors as a therapeutic modality.Acc Chem Res :462-
469.

Leto G, Tumminello F M, Crescimanno M, Flandina C, Gebbia N. 2004,Cathepsin D

expression levels in nongynecological solid tumors: clinical and therapeutic
implications.Clin Exp Metastasis:91-106.

Li N, Chen X, Liao J, et al. 2002 Inhibition of 7,12-dimethylbenz[a]anthracene (DMBA)-

induced oral carcinogenesis in hamsters by tea and curcumin.
Carcinogenesis.;23(8):1307-1313.

Liao, S., Lin, J., Dang, M. T., Zhang, H., Kao, Y. H., Fukuchi, J and Hiipakka, R. A.,
2001, Growth suppression of hamster flank organs by topical application of catechins,
alizarin, curcumin, and myristoleic acid. Arch. Dermatol. Res., 293, 200–205.

Liang J, Huang M, Duan W, Yu X Q, Zhou S. 2007, Design of new oxazaphosphorine

anticancer drugs. Curr Pharm Des.;:963-78.

Lin C C, Lee C W, Chu T H, Cheng CY, Luo S F, Hsiao L D, Yang C M. 2007,

Transactivation of Src, PDGF receptor, and Akt is involved in IL-1beta-induced ICAM-1
expression in A549 cells. J Cell Physiol. 771-80.

Lim G P, Chu T, Yang F, Beech W, Frautschy S A, Cole G M. 2001, The curry spice
curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic
mouse. J Neurosci.;21(21):8370-8377.

Lim, G. P., Chu, T., Yang, F., Beech, W., Frantschy, S. A. and Cole, G. M., 2001,The
curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer
transgenic mouse. J. Neurosci., 21, 8370–8377.
Limasset B, le Doucen C, Dore J C, Ojasoo T, Damon M, Crastes de Paulet A. 1993,
Effects of flavonoids on the release of reactive oxygen species by stimulated human
neutrophils. Multivariate analysis of structure-activity relationships (SAR). Biochem
Pharmacol.:1257-1271.

Lippman S M, Benner S E, Hong W K. Chemoprevention. Strategies for the control of

cancer. 1993, Cancer.:984-990.

Lorimer I A, Wikstrand C J, Batra S K, Bigner DD, Pastan I. 1995, Immunotoxins that

target an oncogenic mutant epidermal growth factor receptor expressed in human tumors.
Clin Cancer Res.:859-864.

Li YL, Xu W F, 2004, Design, synthesis, and activity of caffeoyl pyrrolidine derivatives

as potential gelatinase inhibitors.Bioorg Med Chem. :5171-5180

Lin L, Shi Q, Nyarko A K, Bastow K F, Wu C C, Su C Y, Shih CC, Lee K H. 2006,

Antitumor agents. 250. Design and synthesis of new curcumin analogues as potential
anti-prostate cancer agents.J Med Chem.:3963-72.

Lutomski, J., Kedzia, B. and Debska, W., 1974, Effect of an alcohol extract and of active
ingredients from Curcuma longa on bacteria and fungi. Planta Med., 26, 9–19.

Lüftner D, Possinger K. 2005, Pegfilgrastim -- rational drug design for the management
of chemotherapy-induced neutropenia. Onkologie.:595-602.

Mahady, G. B., Pendland, S. L., Yun, G. and Lu, Z. Z., 2002, Turmeric (Curcuma longa)
and curcumin inhibit the growth of Helicobacter pylori, of group 1 carcinogen.
Anticancer Res., 22,4179–4181.

Mahakunakorn, P., Tohda, M., Murakami, Y., Matsumoto, K., Watanabe,H. and
Vajragupta, O., 2003, Cytoprotective and cytotoxic effects of curcumin: dual action on
H2O2 induced oxidative cell damage in NG108-15 cells. Biol. Pharm. Bull., 26, 725–
728.

Mahmoud N N, Carothers A M, Grunberger D, et al. 2000, Plant phenolics decrease

intestinal tumors in an animal model of familial adenomatous polyposis.
Carcinogenesis.;21(5):921-927.

Mall M, Kunzelmann K. 2005, Correction of the CF defect by curcumin: hypes and

disappointments. Bioessays.;27(1):9-13.

Martin-Cordero, C., Lopez-Lazaro, M., Galvez, M. and Ayuso, M. J., 2003, Curcumin as
a DNA topoisomerase II poison. J. Enzyme Inhib. Med. Chem., 18, 505–509.
Masuda, T., Maekawa, T., Hidaka, K., Bando, H., Takeda Y. and Yamaguchi, H., 2001,
Chemical studies on antioxidant mechanisms of curcumin: analysis of oxidative coupling
products from curcumin and linoleate. J. Agric. Food Chem., 49, 2539–2547.

Mazumdar, A., Raghavan, K., Weinstein, J., Kohn, K. W. and Pommer, Y., 1995,
Inhibition of human immunodeficiency virus type-1 integrase by curcumin. Biochem.
Pharmacol., 49, 1165–1170.

McDonald E R 3rd, Chui P C, Martelli P F, Dicker D T, El-Deiry W S. 2001,

Death domain mutagenesis of KILLER/DR5 reveals residues critical for apoptotic
signaling. J Biol Chem. :14939-45.

Menon LG, Kuttan R, Kuttan G.1999, Anti-metastatic activity of curcumin and catechin.
Cancer Lett.;141(1-2):159-165.

Meresse P, Dechaux E, Monneret C, Bertounesque E. 2004,Etoposide: discovery and

medicinal chemistry.Curr Med Chem:2443-66.

Misra, S. K. and Sahu, K. C., 1977, Screening of some indigenous plants for antifungal
activity against dermatophytes. Indian J. Pharmacol., 9, 269–272.

Moody T W, Mantey SA, Pradhan T K, Schumann M, Nakagawa T, Martinez A, Fuselier

J, Coy D H, Jensen RT. 2004, Development of high affinity camptothecin-bombesin
conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells.J
Biol Chem. :23580-9.

Moos P J, Edes K, Mullally J E, Fitzpatrick F A. 2004, Curcumin impairs tumor

suppressor p53 function in colon cancer cells. Carcinogenesis.;25(9):1611-1617.

Montagut C, Rovira A, Albanell J. 2006, The proteasome: a novel target for anticancer
therapy. Clin Transl Oncol. May;8(5):313-7.

Mulshine JL, Birrer M, Treston AM, Scott F, Quinn K, Avis I, Cuttitta F. 1992,Growth
factors and other targets for rational application as intervention agents.Adv Exp Med
Biol.;320:81-8.

Nair U, Bartsch H. 2001, Metabolic polymorphisms as susceptibility markers for lung

and oral cavity cancer.IARC Sci Publ.;154:271-90.

Nanji A A, Jokelainen K, Tipoe G L, Rahemtulla A, Thomas P, Dannenberg A J.

2003Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression
of NF-kappa B-dependent genes. Am J Physiol Gastrointest Liver Physiol.;284(2):G321-
327.

Narayanan B A. 2006, Chemopreventive agents alters global gene expression pattern:

predicting their mode of action and targets. Curr Cancer Drug Targets:711-27
Newell D R. 2005, How to develop a successful cancer drug--molecules to medicines or
targets to treatments?Eur J Cancer. :676-82.

Nirmala, C. and Puvanakrishnan, R., 1996, Protective role of curcumin against

isoproterenol-induced myocardial infarction in rats. Mol.Cell. Biochem., 159, 85–93.

Novotny L, Szekeres T. 2003, Cancer therapy: new targets for chemotherapy.

Hematology. Jun;8(3):129-37.

Ohashi Y, Tsuchiya Y, Koizumi K, Sakurai H, Saiki I. 2003, Prevention of intrahepatic

metastasis by curcumin in an orthotopic implantation model. Oncology.;65(3):250-258.

Olden K, Newton S A, Nagai T, Yasuda Y, Grzegorzewski K, Breton P, Oredipe O, White

S L. 1992, The use of novel antineoplastic agents to inhibit the growth and metastasis of
malignant melanoma and other cancers.Pigment Cell Res.;Suppl 2:219-33

Park S, Lee D K, Yang C H. 1998, Inhibition of fos-jun-DNA complex formation by

dihydroguaiaretic acid and in vitro cytotoxic effects on cancer cells.Cancer Lett. 23-8.

Pan, M-H., Huang, T-M. and Lin, J-K., 1999, Biotransformation of curcumin through
reduction and glucoronidation in mice. Drug Metabol. Dispos., 27, 486–494.

Patil, T. N. and Srinivasan, M., 1971, Hypocholesteremic effect of curcumin in induced-

hypercholesteremic rats. Indian J. Exp. Biol., 9, 167–169.

Peacock A F, Parsons S, Sadler P J. 2007, Tuning the hydrolytic aqueous chemistry of

osmium arene complexes with N,O-chelating ligands to achieve cancer cell cytotoxicity.
J Am Chem Soc.:3348-57.

Pereira M A, Grubbs C J, Barnes L H, et al. 1996, Effects of the phytochemicals,

curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-
imethylbenz[a]anthracene-induced mammary cancer in rats. Carcinogenesis.;17(6):1305-
1311.

Perkins S, Verschoyle R D, Hill K, et al. 2002, Chemopreventive efficacy and

pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous
polyposis. Cancer Epidemiol Biomarkers Prev.;11(6):535-540.

Pesic M, Markovic JZ, Jankovic D, Kanazir S, Markovic ID, Rakic L, Ruzdijic S. 2006
Induced resistance in the human non small cell lung carcinoma (NCI-H460) cell line in
vitro by anticancer drugs.J Chemother. 66-73.

Phan, T. T., See, P., Lee, S. T. and Chan, S. Y., 2001, Protective effects of curcumin
against oxidative damage on skin cell in vitro: its implication for wound healing. J.
Trauma, 51, 927–931.
Piwocka, K., Jaruga, E., Skierski, J., Gradzka, I. and Sikora, E., 2001, Effect of
glutathione depletion on caspase-3 independent apoptosis pathway induced by curcumin
in Jurkat cells. Free Radic.Biol. Med., 31, 670–678.

Platel, K. and Srinivasan, K., 2000, Influence of dietary spices and their active principles
on pancreatic digestive enzymes in albino rats.Nahrung, 44, 42–46.

Platel, K. and Srinivasan, K., 1996, Influence of dietary spices or their active principles
on digestive enzymes of small intestinal mucosa in rats. Int. J. Food Sci. Nutr., 47, 55–59.

Plummer S M, Holloway K A, Manson M M, et al. 1999 Inhibition of cyclo-oxygenase 2

expression in colon cells by the chemopreventive agent curcumin involves inhibition of
NF-kappaB activation via the NIK/IKK signalling complex. Oncogene.;18(44):6013-
6020.

Prasad, D. N., Gupta B., Srivastava, R. K. and Satyavati, G. V., 1976, Studies on
ulcerogenic activity of curcumin. Indian J. Physiol. Pharmacol., 20, 92.

Padrón J M, Miranda P O, Padrón J I, Martín V S. 2006, Beta'-hydroxy-alpha,beta-

unsaturated ketones: a new pharmacophore for the design of anticancer drugs. Bioorg
Med Chem Lett. :2266-9.

Pulla Reddy, Ach. and Lokesh, B. R., 1994, Effect of dietary turmeric (Curcuma longa)
on iron-induced lipid peroxidation in the rat liver.Food Chem. Toxicol., 32, 279–283.

Pulla Reddy, Ach. and Lokesh, B. R., 1992, Studies on spice principles as antioxidant in
the inhibition of lipid peroxidation of rat liver microsomes. Mol. Cell. Biochem., 111,
117–124.

Punithavathi, D., Venkatesan, N. and Babu, M., 2000, Curcumin inhibition of bleomycin
induced pulmonary fibrosis in rats. Br. J. Pharmacol., 131, 169–172.

Quemener V, Blanchard Y, Chamaillard L, Havouis R, Cipolla B, Moulinoux JP. 1994,

Polyamine deprivation: a new tool in cancer treatment.
Anticancer Res.443-8.

Ramprasad, C. and Sirsi, M. 1956, Studies on Indian medicinal plants:Curcuma longa

Linn. – Effect of curcumin and the essential oils of Curcuma longa on bile secretion. J.
Sci. Ind. Res., 15,262–265.

Rao C V, Rivenson A, Simi B, Reddy B S. 1995 Chemoprevention of colon

carcinogenesis by dietary curcumin, a naturally occurring plant phenolic compound.
Cancer Res.;55(2):259-266.
Rao, S. D., Chandrashekhara, N., Satyanarayana, M. N. and Srinivasan,M., 1970, Effect
of curcumin on serum and liver cholesterol levels in the rat. J. Nutr., 100, 1307–1315.

Rashmi, R., Kumar, S. and Karunagaran, D., 2004, Ectopic expression of Hsp 70 confers
resistance and silencing its expression sensitizes human colon cancer cells to curcumin-
induced apoptosis. Carcinogenesis, 25, 179–187.

Rasmussen, H. B., Christensen, S. B., Kuist, L. P. and Karazmi, A., 2000, A simple and
effective separation of the curcumins, the antiprotozoal constituents of Curcuma longa.
Planta Med., 66,396–398.

Radhakrishna Pillai G, Srivastava A S, Hassanein T I, Chauhan D P, Carrier E. 2004,

Induction of apoptosis in human lung cancer cells by curcumin.Cancer Lett.:163-70.

Rasyid A, Lelo A. 1999; The effect of curcumin and placebo on human gall-bladder
function: an ultrasound study. Aliment Pharmacol Ther. 13:245-249.

Rasyid A, Rahman AR, Jaalam K, Lelo A. 2002, Effect of different curcumin dosages on
human gall bladder. Asia Pac J Clin Nutr.;11:314-318.

Ravindranath, V. and Chandrasekhara, N., 1980, Absorption and tissue distribution of

curcumin in rats. Toxicology, 16, 259–265.

Ray S, Chattopadhyay N, Mitra A, Siddiqi M, Chatterjee A. 2003, Curcumin exhibits

antimetastatic properties by modulating integrin receptors, collagenase activity, and
expression of Nm23 and E-cadherin.J Environ Pathol Toxicol Oncol: 49-58.

Rinaldi A L, Morse M A, Fields H W, et al. 2002 Curcumin activates the aryl

hydrocarbon receptor yet significantly inhibits (-)-benzo(a)pyrene-7R-trans-7,8-
dihydrodiol bioactivation in oral squamous cell carcinoma cells and oral mucosa. Cancer
Res.;62(19):5451-5456.

Rithaporn, T., Monga, M. and Rajasekharan, M., 2003, Curcumin: a potential vaginal
contraceptive. Contraception, 68, 219–223.

Roughley, P. J. and Whiting, D. A., 1973, Experiments in the biosynthesis of curcumin. J.

Chem. Soc., 20, 2379–2388.

Robinson T P, Ehlers T, Hubbard IV R B, Bai X, Arbiser J L, Goldsmith D J, Bowen J P.

2003, Design, synthesis, and biological evaluation of angiogenesis inhibitors: aromatic
enone and dienone analogues of curcumin. Bioorg Med Chem Lett. 115-7.

Rodina A, Vilenchik M, Moulick K, Aguirre J, Kim J, Chiang A, Litz J, Clement CC,

Kang Y, She Y, Wu N, Felts S, Wipf P, Massague J, Jiang X, Brodsky JL, Krystal GW,
Chiosis G. 2007, Selective compounds define Hsp90 as a major inhibitor of apoptosis in
small-cell lung cancer. Nat Chem Biol. 498-507.
Ruby, A. J., Kuttan, G., Dinesh Babu, K., Rajasekharan, K. N. and Kuttan, R., 1995,
Antitumor and antioxidant activity of natural curcuminoids.Cancer Lett., 94, 79–83.

Rukkumani, R., Sri Balasubashini, M. and Menon, V. P., 2003, Protective effects of
curcumin and photo-irradiated curcumin on circulatory lipids and lipid peroxidation
products in alcohol and polyunsaturated fatty acid-induced toxicity. Phytother. Res., 17,
925–929.

Sajithlal, G. B., Chittra, P. and Chandrakasan, G., 1998, Effect of curcumin on the
advanced glycation and cross-linking of collagen in diabetic rats. Biochem. Pharmacol.,
56, 1607–1614.

Sambaiah, K., Ratankumar, S., Kamanna, V. S., Satyanarayana, M. N. and Rao, M. V. L.

1982,, Influence of turmeric and curcumin on growth,blood constituents and serum
enzymes in rats. J. Food Sci. Technol., 19, 187–190.

Satoskar R R, Shah S , Shenoy S G. 1986, Evaluation of anti-inflammatory property of

curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin
Pharmacol Ther Toxicol. 24(12):651-654.

Schweinitz A, Steinmetzer T, Banke IJ, Arlt MJ, Stürzebecher A, Schuster O, Geissler A,

Giersiefen H, Zeslawska E, Jacob U, Krüger A, Stürzebecher J. 2004, Design of novel
and selective inhibitors of urokinase-type plasminogen activator with improved
pharmacokinetic properties for use as antimetastatic agents.
J Biol Chem.:33613-22.

Schüller H M. 1991, The signal transduction model of carcinogenesis.Biochem

Pharmacol. Sep 27;42(8):1511-23.

Sen S, Sharma H, Singh N. 2005,Curcumin enhances Vinorelbine mediated apoptosis in

NSCLC cells by the mitochondrial pathway.Biochem Biophys Res Commun. :1245-52.

Shah BH, Nawaz Z, Pertani SA, et al. 1999, Inhibitory effect of curcumin, a food spice
from turmeric, on platelet-activating factor- and arachidonic acid-mediated platelet
aggregation through inhibition of thromboxane formation and Ca2+ signaling. Biochem
Pharmacol.;58(7):1167-1172.

Shao, Z. M., Shen, Z. Z., Liu, C. H., Sartippour, M. R., Go, V. L.,Heber, D. and Nguyen,
M., 2002, Curcumin exerts multiple suppressive effects on human breast carcinoma
cells. Int. J. Cancer, 98,234–240.

Sharma RA, Euden SA, Platton SL, et al. 2004, Phase I clinical trial of oral curcumin:
biomarkers of systemic activity and compliance. Clin Cancer Res.;10(20):6847-6854.
Sharma RA, Gescher AJ, Steward WP. 2005, Curcumin: The story so far. Eur J
Cancer.;41(13):1955-1968.

Sharma, O. P., 1976, Antioxidant activity of curcumin and related compounds.Biochem.

Pharmacol., , 25, 1811–1812.

Shigeoka Y, Igishi T, Matsumoto S, Nakanishi H, Kodani M, Yasuda K, Hitsuda Y,

Shimizu E. 2004,Sulindac sulfide and caffeic acid phenethyl ester suppress the motility of
lung adenocarcinoma cells promoted by transforming growth factor-beta through Akt
inhibition.J Cancer Res Clin Oncol. 146-52.

Shishodia S, Potdar P, Gairola C G, Aggarwal B B. 2003, Curcumin (diferuloylmethane)

down-regulates cigarette smoke-induced NF-kappaB activation through inhibition of
IkappaBalpha kinase in human lung epithelial cells: correlation with suppression of
COX-2, MMP-9 and cyclin D1. Carcinogenesis. 1269-79.

Shukla, Y. and Arora, A., 2003, Suppression of altered hepatic foci development by
curcumin in Wistar rats. Nutr. Cancer, 45, 53–59.

Shukla, Y., Arora, A. and Taneja, P., 2002, Antimutagenic potential of curcumin on
chromosomal aberrations in Wistar rats. Mutat. Res., 515, 197–202.

Sidhu, G. S. et al., 1999, Curcumin enhances wound healing in streptozotocin induced

diabetic rats and genetically diabetic mice. Wound Repair Regen., 7, 362–374.

Sikora, E., Bielak-Zmijewska, A., Piwocka, K., Skierski, J. and Radziszewska, E., 1997,
Inhibition of proliferation and apoptosis of human and rat T lymphocytes by curcumin, a
curry pigment. Biochem.Pharmacol., 54, 899–907.

Sinkule J A, Rosen S T, Radosevich J A. 1991,Monoclonal antibody 44-3A6 doxorubicin

immunoconjugates: comparative in vitro anti-tumor efficacy of different conjugation
methods. Tumour Biol.;12(4):198-206.

Shim J S, Kwon H J. 2004, Chemical genetics for therapeutic target mining.Expert Opin
Ther Targets. :653-61.

Shivapurkar N, Reddy J, Chaudhary P M, Gazdar A F. 2003, Apoptosis and lung cancer: a

review. J Cell Biochem:885-98

Singh SV, Hu X, Srivastava SK, et al. 1998, Mechanism of inhibition of benzo[a]pyrene-

induced forestomach cancer in mice by dietary curcumin. Carcinogenesis.;19(8):1357-
1360.

Singh, S. and Aggarwal, B. B., 1995, Activation of transcription factor NF-kappa B is

suppressed by curcumin (diferuloylmethane). J. Biol.Chem., 270, 24995–25000.
Singletary K, MacDonald C, Iovinelli M, Fisher C, Wallig M. 1998, Effect of the beta-
diketones diferuloylmethane (curcumin) and dibenzoylmethane on rat mammary DNA
adducts and tumors induced by 7,12-dimethylbenz[a]anthracene. Carcinogenesis.;
19(6):1039-1043.

Sinha, M., Mukherjee, B. P., Mukherjee, B. and Dasgupta, S. 1974, R.,Study on the 5-
hydroxytryptamine contents in guinea pig stomach with relation to phenylbutazone
induced gastric ulcers and the effects of curcumin thereon. Indian J. Pharmacol., 6, 87–
96.

Sinha, M., Mukherjee, B. P., Mukherjee, B., Sikdar, S. and Dasgupta,S. R., 1975, Study
of the mechanism of action of curcumin; an antiulcer agent. Indian J. Pharmacol., 7, 98.

Somasundaram S, Edmund N A, Moore D T, Small GW, Shi Y Y, Orlowski R Z. 2002,

Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast
cancer. Cancer Res.;62(13):3868-3875.

Song Y, Sonawane N D, Salinas D, et al. 2004, Evidence against the rescue of defective
DeltaF508-CFTR cellular processing by curcumin in cell culture and mouse models. J
Biol Chem.;279(39):40629-40633.

Sone S, Shinohara T, Nishioka Y, Yano S. 2001, Symposium on molecular pathogenesis

of respiratory diseases and its clinical implication. 4. Molecular pathogenesis of lung
cancer and its molecular targeted therapy.
Intern Med. 167-70.

Song, E. K. et al., 2001, Diarylheptanoids with free radical scavenging and hepato
protective activity in vitro from Curcuma longa. Planta Med., 67, 876–877.

Sreejayan N, Rao M N. 1996, Free radical scavenging activity of curcuminoids.

Arzneimittelforschung.;46(2):169-171.

Sreejayan Rao, M. N., 1994, Curcuminoids as potent inhibitors of lipid peroxidation. J.

Pharm. Pharmacol., 46, 1013–1016.

Sreejayan, Rao M N. 1997, Nitric oxide scavenging by curcuminoids. J Pharm

Pharmacol.;49(1):105-107.

Srihari Rao, T., Basu, N. and Siddqui, H. H., 1982 Anti inflammatory activity of
curcumin analogues. Indian J. Med. Res., , 75, 574–578.

Srivastava K C, Bordia A, Verma S K. 1995, Curcumin, a major component of food spice

turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in
human blood platelets. Prostaglandins Leukot Essent Fatty Acids.;52(4):223-227.
Srivastava, R. and Srimal, R. C., 1985, Modification of certain inflammation-induced
biochemical changes by curcumin. Indian J. Med.Res., 81, 215–223.

Srivastava, R., Dikshit, M., Srimal, R. C. and Dhawan, B. N., 1985, Antithrombotic
effect of curcumin. Thromb. Res., 40, 413–417
.
Steele V E, Hawk E T, Viner J L, Lubet R A. 2003, Mechanisms and applications of non-
steroidal anti-inflammatory drugs in the chemoprevention of cancer. Mutat Res.;523-
524:137-144.

Stewart Z A, Westfall M D, Pietenpol J A. 2003, Cell-cycle dysregulation and anticancer

therapy. Trends Pharmacol Sci.;24(3):139-145.

Subramanian, M., Sreejayan Rao, M. N. A., 1994, Devasagayam, T. P. A.and Singh, B.

B., Diminution of singlet oxygen induced DNA damage by curcumin and related
antioxidants. Mutat. Res., 311,249–255.

Sumbilla, C., Lewis, D., Hammerschmidt, T. and Inesi, G., 2002, The slippage of the
Ca2+ pump and its control by anions and curcumin in skeletal and cardiac sarcoplasmic
reticulum. Biol. Chem., 277, 13900–13906.

Surh, Y. J., 2002, Anti-tumor promoting potential of selected spice ingredients with
antioxidative and anti-inflammatory activities: a short review. Food Chem. Toxicol., 40,
1091–1097.

Suryanarayana, P., Krishnaswamy, K. and Reddy, G. B. 2003, Effect of curcumin on

galactose-induced cataractogenesis in rats. Mol.Vis., 9, 223–230.

Susan M, Rao M N. 1992, Induction of glutathione S-transferase activity by curcumin in

mice. Arzneimittelforschung.;42(7):962-964.

Taher, M. M., Lammering, G., Hershey, C. and Valerie, K., 2003, Curcumin inhibits
ultraviolet light induced human immunodeficiency virus gene expression. Mol. Cell
Biochem., 254, 289–297.

Takaba K, Hirose M, Yoshida Y, Kimura J, Ito N, Shirai T. 1997, Effects of n-

tritriacontane-16,18-dione, curcumin, chlorphyllin, dihydroguaiaretic acid, tannic acid
and phytic acid on the initiation stage in a rat multi-organ carcinogenesis model.
Cancer Lett. 39-46.

Tamura K, Fukuoka M. 2003, Molecular target-based cancer therapy: tyrosine kinase

inhibitors. Int J Clin Oncol. :207-11

Tietze LF, Major F, Schuberth I, Spiegl DA, Krewer B, Maksimenka K, Bringmann G,

2007, Magull J. Selective treatment of cancer: synthesis, biological evaluation and
structural elucidation of novel analogues of the antibiotic CC-1065 and the
duocarmycins. Chemistry.; 4396-409.

Thaloor D, Singh A K, Sidhu G S, Prasad P V, Kleinman H K, 1998 Maheshwari R K.

Inhibition of angiogenic differentiation of human umbilical vein endothelial cells by
curcumin. Cell Growth Differ.;9(4):305-312.

Thapliyal R, Maru G B. 2001, Inhibition of cytochrome P450 isozymes by curcumins in

vitro and in vivo. Food Chem Toxicol.;39(6):541-547.

Thiyagarajan, M. and Sharma, S. S., 2004, Neuroprotective effect of curcumin in middle

cerebral artery occlusion induced focal cerebral ischemia in rats. Life Sci., 74, 969–985.

Thomas T, Balabhadrapathruni S, Gallo M A, Thomas T J. 2002, Development of

polyamine analogs as cancer therapeutic agents.Oncol Res.: 123-35.

Torchilin V P, Lukyanov A N, Gao Z, Papahadjopoulos-Sternberg B. 2003,

Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs.
Proc Natl Acad Sci U S:6039-44.

Tsvetkov P, Asher G, Reiss V, Shaul Y, Sachs L, Lotem J. 2005, Inhibition of

NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the
natural phenolic compound curcumin. Proc Natl Acad Sci U S A.;102(15):5535-5540.

Vajragupta, O., Boonchoong, P., Watanabe, H., Tohda, M., Kummasud,N. and Sumanont,
Y., 2003, Manganese complexes of curcumin and its derivatives: evaluation for the
radical scavenging ability and neuroprotective activity. Free Radic. Biol. Med., 35, 1632–
1644.

Velpandian T, Jasuja R, Bhardwaj R K, Jaiswal J, Gupta S K. 2001; Piperine in food:

interference in the pharmacokinetics of phenytoin. Eur J Drug Metab Pharmacokinet.
26(4):241-247.

Vopel, G., Gaisbaver, M. and Winkler, W., 1990, Phytotherapie in der Praxis. Deutscher
Arzteverlag, Kolu, 74.

Wahlstrom, B. and Blennow, G., 1978, A study on the fate of curcumin in the rat. Acta
Pharmacol. Toxicol., 43, 86–92.

Wawrzynczak E J, Zangemeister-Wittke U, Waibel R, Henry R V, Parnell G D, Cumber A

J, Jones M, Stahel R A. 1992 , Molecular and biological properties of an abrin A chain
immunotoxin designed for therapy of human small cell lung cancer.
Br J Cancer.:361-6.

Webb M S, Johnstone S, Morris T J, Kennedy A, Gallagher R, Harasym N, Harasym T,

Shew C R, Tardi P, Dragowska W H, Mayer LD, Bally M B. 2007, In vitro and in vivo
characterization of a combination chemotherapy formulation consisting of vinorelbine
and phosphatidylserine. Eur J Pharm Biopharm. :289-99.

Wei F, Zhao B X, Huang B, Zhang L, Sun C H, Dong W L, Shin D S, Miao J Y. 2006,

Design, synthesis, and preliminary biological evaluation of novel ethyl 1-(2'-hydroxy-
3'-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxylate.

Wesche H, Xiao S H, Young S W. 2005, High throughput screening for protein kinase
inhibitors. Comb Chem High Throughput Screen. :181-95.

Woo, J. H. et al., 2003, Molecular mechanisms of curcumin-induced cytotoxicity:

induction of apoptosis through generation of reactive oxygen species, down-regulation of
Bcl-XL and IAP, the release of cytochrome c and inhibition of Akt. Carcinogenesis, 24,
1199–1208.

Worden FP, Kalemkerian G P. 2000, Therapeutic advances in small cell lung cancer.
Expert Opin Investig Drugs. :565-79.

Wuthi-Udomler, M., Grisanapan, W., Luanratana, O. and Caichompoo, W., 2000,

Antifungal activity of Curcuma longa grown in Thailand. Southeast Asian J. Trop. Med.
Public Health, 31,178–182.

Yamaguchi K. 2004, [Ectopic hormone-producing tumors--research and clinics]

Nippon Rinsho:983-6

Yamada Y, Pannell R, Forster A, Rabbitts T H. 2002, The LIM-domain protein Lmo2 is a

key regulator of tumour angiogenesis: a new anti-angiogenesis drug target.
Oncogene.:1309-15. :

Yang F, Lim G P, Begum A N, et al. 2005, Curcumin inhibits formation of amyloid beta
oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol
Chem.;280(7):5892-5901.

Yegnanarayan, R., Saraf, A. P. and Balwani, J. H., 1976, Comparison of anti-

inflammatory activity of various extracts of Curcuma longa (Linn).Indian J. Med. Res.,
64, 601–608.

Yoshida S, Kawaguchi H, Sato S, Ueda R, Furukawa K. 2002, An anti-GD2 monoclonal

antibody enhances apoptotic effects of anti-cancer drugs against small cell lung cancer
cells via JNK (c-Jun terminal kinase) activation. Jpn J Cancer Res. 816-24.

Yuasa M, Oyaizu K, Horiuchi A, Ogata A, Hatsugai T, Yamaguchi A, Kawakami H. 2004,

Liposomal surface-loading of water-soluble cationic iron(III) porphyrins as anticancer
drugs.Mol Pharm. :387-9.
Yang P, Yang Q, Qian X, Tong L, Li X. 2006, Isoquino[4,5-bc]acridines: design,
synthesis and evaluation of DNA binding, anti-tumor and DNA photo-damaging ability.
J Photochem Photobiol B. 221-6.

Zhang X and Chang A, 2006,Somatic mutations of the epidermal growth factor receptor
and non-small-cell lung cancer.J Med Genet. 44(3):166-72.

Zhao Y, Zhang W, Kho Y, Zhao Y,2004, Proteomic analysis of integral plasma membrane
proteins.Anal Chem. 1817-23.

Zumkeller W, Schofield P N. 1995, Growth factors, cytokines and soluble forms of

receptor molecules in cancer patients. Anticancer Res. :343-8.