Klotho Combinations: Gene Therapy as a Prospective Efficient

Treatment of Non Small Cell Lung Cancer

ABSTRACT:
Klotho is one of the natural immunity mechanism that suppress tumor cell growth.
at the normal cell, klotho has a various function such as Wnt signalling pathways
inhibitor, IGF-1 receptor inhibitor and many others. These are Klotho properties
that will be reviewed as a main inhibitor in the tumor cell growth. In the case of non
small cell lung cancer, the expressed of this protein was decreased. the use of
chemotherapy, radiotherapy and surgery already widely used but did not produce
significant result. patients must bear the severe side-effects. This ​article reviewed
the previous researches about the use of klotho combined with sCD40L, the TNF
superfamily, that can decreased the growth of tumor cells. Klotho inhibit more than
one signalling pathways which we expect to slow the growth of tumor cells. because
of the tumor cells develop through so many and complex pathways, it is almost
impossible to eradicate the whole cell tumors. what we can do is to slowing down the
growth of tumor cells.
.
Cancer is the uncontrolled growth of abnormal cells in the body. C​ancer is a leading
cause of death worldwide, accounting for 7.6 million deaths (around 13% of all deaths) in
2008. the most cancer caused death are lung cancer, colon cancer, breast cancer, liver
cancer and stomach cancer. ​Deaths caused by lung cancer, there were 1.37 million cases
in 2008. This case happens in many developing countries, including in Indonesia.
Compounded by the fact that men are smokers.
Since the year 1999-2009 there were more than 100,000 each year of lung cancer
incidence in all ethnicities and races throughout the world. Along with the increasing
number of patients with lung cancer in the Asia Pacific region, led us to study the
literature on cancer therapy that can be developed for therapeutic advances for patients
with lung cancer, in particular combination therapy. Our hope this can be an alternative
therapy rather than conventional therapies such as chemotherapy or surgery.
Conventional therapies practiced today still can not provide satisfactory results within a
short period of time and in patients with metastatic cancer. Hopefully, treatment with
combination therapy using Klotho as an enzyme have a better results and improve
patient quality of life.

INTRODUCTION
Cancer has been one of the most difficult abnormalities to treat. It is defined as
the uncontrolled growth of abnormal cells in the body​[1]​. The normal cycle of cell has
four stages: Stages that occur during mitosis is divided into four consecutive phases,
namely prophase, metaphase, anaphase, telophase. The cleavage phase between one
another is called interphase. During interphase is divided into three periods aims to meet
the growing needs of the cell and perform a variety of synthesis before entering the next
division.
1) Primary growth phase (G1)
The newly formed cell organelles first stage of growth - that is inside the cell
organelles such as mitochondria, endoplasmic reticulum, Golgi complex and
other
organelles reproduce themselves to support the work of the cell.
2) Synthesis Phase (S)
At this stage, the cells synthesize mainly the synthesis of genetic material, such
as
DNA.
3) Secondary growth phase ( G2 )
Towards the next mitosis, cells perform a second growth by increasing its
organelles
This cycle is started with gene called proto-oncogenes and regulated by tumor suppressor
genes, DNA repair genes and anti-apoptotic genes. These genes controls every mitosis
that the cell made. However, in every mitosis, there is one gene undergoes mutation.
Sometimes this mutation is deleted by pro-apoptotic gene expression, but in cancer, this
process leads to a failure in regulating its growth hence creating cells that undergo
mitosis and “escaping” apoptosis. The pathogenesis of this uncontrolled growth involves
many signalling pathways, many genes and their expressions. One of the signalling
pathways is the Akt pathway. Akt regulates cell growth and cell proliferation directly or
indirectly. It is a major mediator of cell survival through direct inhibition of pro-apoptotic
signals​[3]​. This fact has encouraged researchers to find that gene therapy might responds
better to cancer than to solely use chemotherapy or radiotherapy. The current chemo and
radiotherapy both have various severe side-effect. Those treatments usually cannot differ
between a healthy cell or a cancerous cell, hence they also endanger the healthy cell of
the body.
Klotho gene therapy that combine with sCD04L Klotho hope will be a new breakthrough
in cancer treatment
A discovery about an anti-aging KL gene which is expressed to be a membrane protein
klotho, shows an apoptotic activity in cell cycle when it is being overexpressed. This
protein also arrests the S phase of the cell cycle. Recent researches show that klotho can
be used as a additional therapy as well as the primary therapy itself.
In normal cell, klotho is an anti-aging protein which is able to extend lifespan
when overexpressed and its deficiency may results in multiple aging-like phenotypes​[5]​.
Meanwhile, tumorigenesis are epidemiologically high within the older age groups (55
year-old and older) and so, creating a perspective that anti-aging molecule can lower the
incidence of cancer.​[5]
The apoptotic and proliferation inhibition activity of overexpressed klotho in
cancer have been published. It inhibits several pathways such as Akt pathway, IGF-1
pathway and Wnt pathway. The transfection of its mRNA in lung cancer cell is shown to
inhibits the phosphorylation of IGF-1R.

Image 1.
 In addition, it also inhibits the motility of cancer cells which is important in
​
metastasis of the cancer [4]
Klotho can be used as a combination therapy in non small cell lung cancer.
Klotho is combined with Cisplatin, a first-line drug for lung cancer chemotherapy and
shows a cumulative ability to enhance apoptosis of cancer cells​[6​]

CONCLUSIONS:​ A wide variety of topics and methodological limitations made

comparisons between studies difficult. Strategies to increase the generalizability of the
study presented the future of cancer therapy. There is a great opportunity to study gene
combination therapy primarily on molecular studies in patients with lung cancer.