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Breast

Cancer Protocols
Isolates, Herbs and Formulations
Protects normal cells and
tissues against damage Enhances the potency of
caused by chemo or chemo and radiotherapy
radiotherapy

TCM as a
Complementary Reduces inammation
Prolongs life span and
and reduces or stops
QoL in late stage cancer Therapy for angiogenesis
Cancer

Improves quality of life,


Improves general
physically and mentally.
condition and fatigue,
Allows patients to feel
increases body resistance
some control

drdweber@panaxea.com 2 16/12/14
MeSH Search & Databases
* ("breast neoplasms"[MeSH Terms] OR ("breast"[All Fields] AND
"neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR
("breast"[All Fields] AND "cancer"[All Fields]) OR "breast
cancer"[All Fields]) AND herbs[All Fields] This search provided 132
articles
* ("breast neoplasms"[MeSH Terms] OR ("breast"[All Fields] AND
"neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR
("breast"[All Fields] AND "cancer"[All Fields]) OR "breast
cancer"[All Fields]) AND supplements[All Fields] produced 806
articles
* Traditional Chinese Medicine Information Database:
http://tcm.cz3.nus.edu.sg/group/tcm-id/tcmid_ns.asp.
http://www.megabionet.org/tcmid/ 16/12/14
Bio-Active
Most modern medicines
clinically available for cancer
treatments are expensive and
known for their toxicity and
serious adverse reactions.
It is important to provide
scientic evidence for the
benet of bioactive
constituents used in ancient
systems of medicine and
identify novel compounds/
molecules from natural sources
(Swaroop et al., 2014). 4 16/12/14
CM & Cancer
* According to the theory of Chinese medicine (CM), the
evaluation of how to treat cancer with CM is a criterion of
whether the patient's subjective symptoms are being
improved or not, which cannot necessarily be proven by
Western medicine (WM).
* On the one hand, almost all cancer patients in China would
turn to CM treatment; on the other hand, valid evidences in
the CM eld cannot be oered to convince specialists in the
WM eld, and the eectiveness of CM cannot be explained
either (Yang & Liao, 2010).

drdweber@panaxea.com 5 16/12/14
CM & Cancer
* Before a uniform curative eect evaluation standard comes
out and is accepted, the up-to-date indices like disease
control rate (DCR), time-to-progression (TTP), Karnofsky
performance score (KPS) , body weight, and relevant main
symptoms of disease could be used as short-term standards.
* While indexes of progression-free survival (PFS), time-to-
progression (TTP), disease-free survival (DFS), overall survival
(OS) could be used as long-term standards. Such methods
could both represent the advantages of CM, and be accepted
by WM (Yang & Liao, 2010).

drdweber@panaxea.com 6 16/12/14
Breast Cancer
* Every year, among the 1.2 million women diagnosed with breast
cancer worldwide, 500 thousand cases die of the disease. Along
with a sharp increase in life expectancy, expansion of urbanisation
and adaptation of western lifestyle, the increase in incidence rates is
even more obvious in developing countries (Hortobagyi et al, 2005;
Schulz et al, 2008).
* In China, the number of cases increased by 38.5% from 2000 to 2005.
Compared with the early surveys in the 1990s, breast cancer
accounted for the largest increase in mortality rates in 2005 (Yang et
al, 2005).
* In 2009, breast cancer was the most common cancer in Australian
women, accounting for 27.4 per cent of all new cancers in women,
with the average age of 60.7 years and with the risk of 1 in 8 women
before 85 year old 7 16/12/14
Breast Cancers
* Between 65 to 75 per cent of breast cancers are hormone
receptor-positive.
* About 15 to 20 per cent of all breast cancers are HER2+
* About 15-20 per cent of all breast cancers in the U.S. are
TNBC.
* BRCA1 and BRCA2 mutations account for about 20 to 25 per
cent of hereditary breast cancers and about 5 to 10 per cent
of all breast cancers.
* 5 per cent are metastatic when discovered
* 20% to 30% of patients with early breast cancers will
experience relapse with distant metastatic disease
drdweber@panaxea.com 8 16/12/14
Breast Cancer
* There is a 10% to 30% chance of recurrence and metastasis after
treatment. Among the patients with local recurrence, 75% to
93% will eventually develop distant metastasis with an
extremely low 5-year survival rate.
* Chinese medicine adopts an overall therapeutic approach to
treat and prevent recurrence and metastasis, to improve the
immune system of patients, and to strengthen the bodys
susceptibility to diseases. Meanwhile, Chinese medicine also
aims at reducing the side eects of radiotherapy and
chemotherapy, reversing drug resistance and improving quality
of life and survival for patients (Mukherjee et al, 2001; Hsiao et
al., 2010).
drdweber@panaxea.com 9 16/12/14
Breast Cancer & TCM
* Inspecting the history of drug development during the past
half century demonstrates that natural resources represent a
signicant segment on the pharmaceutical market compared
to randomly synthesised compounds. As compiled by the
World Health Organization, more than 21,000 plant species
have been used worldwide in herbal medicines.
* Herbs are an important source for drug development. The
traditional Chinese medicine (TCM) has held and still holds an
important position in primary health care in China and has
been recently recognised by Western countries as a fertile
source for revealing novel lead molecules for modern drug
discovery (Li-Weber 2013).
drdweber@panaxea.com 10 16/12/14
PubMed database from 1960 to 2013
* Since a tremendous interest in acupuncture and herbal
medicine was observed in 2000, the increasing numbers of
published papers per year are apparent. In 2013, more than
90 papers on acupuncture and more than
450 papers on herbal medicines
appeared in the area of cancer prevention
and therapy.

Survey of literature deposited in the PubMed


database from 1960 to 2013 with the keywords
(a) acupuncture or herbal and (b)
acupuncture and cancer or herbal and
cancer.
drdweber@panaxea.com 11 16/12/14
Cancer
* The rst mention of cancer was in the Song Dynasty (ca. 1300
AD).The Chinese word Ai () meaning malignant carcinoma
rst appeared in the ancient medical book Wei Ji Bao Shu (
). According to the theories of TCM, cancer is caused by
imbalances between endogenous physical conditions of the
body and exogenous pathogenic factors.
* The internal condition of the body plays a dominant role in the
onset of cancer. In other words, factors can induce cancer only
when the body's own defence system fails.
* Those pathogenic factors, in Chinese medicine terms, include
accumulated Toxins, Heat and Blood Stasis, and they attack
when a person is in a weak physical condition, without the
strength to resist (Hsiao & Liu, 212 010). 16/12/14
TCM & Breast Cancer
* Traditional Chinese medicine (TCM) may serve as a useful model
for scientic inquiry since there is a standardised system of
diagnostics and therapies, and this discipline is practiced
worldwide. Among the components of TCM, herbal or botanical
agents possess complex biological activities that could aect
many aspects of carcinogenesis such as cell growth and
proliferation, apoptosis, host-tumour interactions, and immune
function and dierentiation (Hsiao & Liu, 2010).
* The theory of TCM coupled with laboratory studies and safety
information can serve as a basis for the design of more
denitive trials of TCM for specic indications in breast cancer
(Cohen et al., 2002).
drdweber@panaxea.com 13 16/12/14
Patterns in Chinese medicine
* A common causative pattern is that excessive Heat from a
decient Liver, combined with Phlegm Dampness due to
Spleen dysfunction, results in the blockage of qi and Blood,
which then "condenses" into breast cancer.
* Another common causative pattern is when Liver Deciency
and Kidney Deciency lead to qi and Blood Deciency.
Chronic qi and Blood deciency then leads to qi Stagnation
and Blood Stasis, which causes the formation of lumps in
the breast (He et al, 2012).

drdweber@panaxea.com 14 16/12/14
Patterns in Chinese medicine
* A third pattern is when qi Stagnation and Phlegm
accumulation lead to excessive Heat Toxins, which then turn
to hard breast lump masses.
* Traditionally, four patterns of breast cancer are dierentiated
for treatment: Liver qi Stagnation (hard masses without pain
and redness); Phlegm Heat Obstruction (hard masses with
sharp pain and redness and swelling); Liver/Kidney
Deciency (hard lumps with swelling and a dimpled
appearance of the breast skin, discharges and indentation of
the nipple); qi/Blood Deciency (hard lumps with swelling,
ruptured abscesses, spreading to the surrounding areas).

drdweber@panaxea.com 15 16/12/14
Patterns DCIS
* Traditional Chinese Medicine
(TCM) dierential diagnoses
for patient with ductal
carcinoma in situ (DCIS).
* Bars represent the frequency
with which various TCM
diagnoses were given
preceding treatment. There are nine instances of spleen qi
deciency, either alone (seven instances) or as heart blood
and spleen qi deciency (two instances) (Dehen, 2013).

drdweber@panaxea.com 16 16/12/14
Breast Cancer & CHM
* The reported incidence of use of complementary and alternative
medicines (CAMs) among women with breast cancer ranges
from 66.7 to 97% (Matthews et al., 2007; Chen et al. 2008)
* Traditional Chinese medicine (TCM) has been growing in
popularity and has oered an important alternative or
complement to health care in many countries. The most
common type of CAM used by Chinese women with breast
cancer is Chinese herbal medicine.
* The majority of patients reported that they had beneted from
the use of CHM (Cui et al., 2004).

drdweber@panaxea.com 17 16/12/14
Breast Cancer & CHM
* Previous studies have disclosed the potential benecial
synergistic eects of the usage of Radix Angelica sinensis
(Seram et al., 2011) or Radix Panax ginseng (Kim et al., 2010)
among women with breast cancer. Jia Wei Xiao Yao San
(Augmented Rambling Powder) was the most frequently
prescribed formula (Lai et al., 2012).
* A previous four-year survey by Cui et al., (2004) indicated that
over 50% of breast cancer patients considered CHP eective in
treating cancer.

drdweber@panaxea.com 18 16/12/14
Breast Cancer & CHM
* Results suggest that, under the coexistence of the conventional
medical treatments and TCM, most breast cancer patients
consumed herbal therapies with the intention of relieving their
treatment-induced symptoms, rather than rejecting standard
cancer treatments (Lai, Wu, Wang, 2012).
* Patients who were younger, married, had higher education or
income, received chemotherapy or radiotherapy, or had
recurrence/metastasis of cancer tended to use CHM more
frequently than other patients.

drdweber@panaxea.com 19 16/12/14
Breast Cancer & CHM
* From the herbal perspective, breast cancer is the local
manifestation of a whole-body disease, referred to as an
intrinsically decient but extrinsically excessive syndrome.
* Based on TCM theories, deciency of Spleen qi, inadequate
source of engendering transformation, deciency of qi and
Blood, and excess of Phlegm-Dampness are believed to be the
main mechanism responsible for development of breast cancer.
* The recurrence and metastasis of breast cancer is considered to
have a close relationship with Liver dysfunctions. These
prescriptions focus on the herbs for nourishing the yin-Blood,
and emolliating and regulating the Liver. Strengthening of
Liver function seems to be the key to successful treatment
(Chen et al., 2011). 20 16/12/14
Breast Cancer & the
Microenvironment
* Many tumours, including breast cancer, are maintained by a
subpopulation of cells that display stem cell properties,
mediate metastasis, and contribute to treatment resistance.
* These cancer stem cells (CSCs) are regulated by complex
interactions with the components of the tumour
microenvironment including mesenchymal stem cells,
adipocytes, tumour associated broblasts, endothelial cells,
and immune cells through networks of cytokines and growth
factors.
* There is now overwhelming evidence that the behaviour of
tumourigenic cells is also highly inuenced by their
microenvironment (Korkaya, Liu, Wicha, 2011).
drdweber@panaxea.com 21 16/12/14
Elevated levels of cytokines and growth factors produced by tumour cells enhance the
proliferation and survival of CSCs, induce angiogenesis, and recruit tumour-associated
macrophages, neutrophils, and mast cells, which secrete additional growth factors,
forming a positive feedback loop that promotes tumour cell invasion and metastasis.

Non-metastatic Metastatic
Tumour Tumour
doi:10.1172/JCI57099

22 16/12/14
Cytokines secreted by cells in the tumour microenvironment regulate BCSC self renewal.
Tumour-associated broblasts (TAFs) and macrophages (TAMs) and MSCs have been
shown to secrete IL-6, IL-8, and CXCL7, which in turn activate Stat3/NF-B signalling,
leading to self renewal of BCSCs. This generates a positive feedback loop between the
tumour microenvironment and tumor cells.

doi:10.1172/JCI57099

drdweber@panaxea.com 23 16/12/14
Isolates, Herbs and Formulas

Treatments

drdweber@panaxea.com 24 16/12/14
The altered protein molecules upon treatments of TCM h25
drdweber@panaxea.com
erbal medicines 16/12/14

and the associated cellular signalling networks.


Network Pharmacology Approach for
CHM Research.
* For the discovery of CHM-derived targets, eect prediction,
mechanism clarication, and new drug assistant discovery using
network pharmacology approach. It analyzes the information
from public data, high-throughput experimental data, and TCM
data and constructs a CHM-TCM syndrome disease
interaction network using technologies of network expansion,
optimisation,
comparison,
knockout, and
addition. Finally, it
carries out
computational and
experimental verications. 26 16/12/14

doi: 10.1155/2013/621423
Triple Negative Breast Cancer

drdweber@panaxea.com 27 16/12/14
TNBC
* Triple-nega+ve breast cancer (TNBCa) (oestrogen receptor
nega+ve, progesterone receptor nega+ve and human
epidermal growth factor receptor 2 (Her2) nega+ve accounts
for 10 to 17 per cent of all breast cancers .
* They tend to be more aggressive than other types of breast
cancer and have poor prognosis. The cause of death of pa+ents
with TNBC is oFen recurrence (30-40% of cases), which
presents as distant metastasis.
* Unfortunately, the an+-tumour ecacy of commonly used
chemotherapeu+c agents for TNBC, including pla+num-based
chemotherapy, is limited due to acquired drug resistance and
toxici+es.
drdweber@panaxea.com 28 16/12/14
TNBC
* Triple negative breast cancer (TNBC) presents clinical
challenges due to unknown aetiology, lack of treatment
targets, and poor prognosis. Lee et al., (2014) examined
combined genetic and nutritional risk models of TNBC in 354
breast cancer cases.
* Results suggest that TNBC was associated with 6 DNA-repair
non-synonymous single nucleotide polymorphisms (nsSNPs);
ERCC4 R415Q (rs1800067), MSH3 R940Q (rs184967), MSH6
G39E (rs1042821), POLD1 R119H (rs1726801), XRCC1 R194W
(rs1799782), and XPC A499V (rs2228000) and/or deciencies
in 3 micronutrients (zinc, folate, and b-carotene).

drdweber@panaxea.com 29 16/12/14
TNBC
* Betulinic Acid (BetA), a pentacyclic triterpene discovered in
1995 from the stem bark of the plant Zizyphus mauri-ana, was
ini+ally reported to be a melanoma-specic cytotoxic agent .
Since then, BetA has been found to exhibit a variety of
biological and medicinal proper+es such as an+-bacterial, an+-
malarial, an+-inammatory and an+-cancer ac+vi+es
* Weber et al (2014) inves+gated the cytotoxic eect of BetA on
breast carcinoma MDA-MB-231 and MDA-MB-468 cell lines.
Furthermore, the an+-inammatory and an+-angiogenic
poten+al of BetA was also examined.

drdweber@panaxea.com 30 16/12/14
BetA
* Possible molecular mechanisms by which BetA induces cell cycle
arrest in breast carcinoma MDA-MB-231 and MDA-MB-468 cell
lines, BetA treated cells were analysed for their DNA content by
propidium iodide staining.
* The data suggest that BetA treatment of MDA-MB-231 cell line
could lead to the inhibi+on of DNA synthesis causing the arrest of
cells in the G2 phase, eventually restraining the prolifera+on of
cells.
* The treatment of MDA-MB-231 cell line with 1 and 10g/mL BetA
lowered the expression of P21, P27, CDK2, CDK6 and Cyclin Dl
whereas 20g/mL BetA lowered the expression of p27 and CDK6
only. BetA treatment of MDA-MB-231 cell line co-cultured with
stromal cells lowered the expression of p21, p27 and Cyclin D1.
31 16/12/14
BetA
* BetA proved to be a potent anti-inammatory, anti-
proliferative and anti-angiogenic agent against breast
carcinoma MDA-MB-231 and MDA-MB-468 cell lines.
* Given the fact that BetA treatment in vitro has been eective
against TNBC, further studies are clearly warranted to
determine its eect in vivo.
* The eectiveness of BetA shows that it may be highly
eective and has great potential in combination with
conventional chemotherapeutic regimes therefore possibly
enhancing the inhibition of tumour proliferation,
inammation and angiogenesis.

drdweber@panaxea.com 32 16/12/14
Panaxea Cory)Cur
* Cory)Cur consists of Yanhusuo (Rhizoma Corydalis) and Ezhu
(Rhizoma Curcumae) and has been an archaic Chinese
medicine prescription since Song Dynasty (960-1279 AD).
Cory)Cur was rst recorded in Ji Feng Pu Ji Fang (vol. 20)
and Zhu Shi Ji Yan Fang (vol. 10) in the Song dynasty, and
used to improve blood circulation, to remove blood stasis,
and to promote circulation for pain relief.
* Both yanhusuo and ezhu could inhibit cancer cell
proliferation, and ezhu induces cancer cell apoptosis,
whereas yanhusuo was shown to inhibit metastasis.

drdweber@panaxea.com 33 16/12/14
Panaxea Cory)Cur
* Extracted by 95% ethanol, the ratio of 3:2 (ezhu to yanhusuo)
results in Cory)Cur having strong synergistic antitumour eects
in MDA-MB-231 cancer cells.
* Findings by Gao et al., (2009) propose that the synergy observed
in the cytotoxic eects of ezhu and yanhusuo in the human
breast cancer cell line, MDA-MB-231, was caused by suppressing
cancer cell proliferation and invasion. The mechanisms should
be related with the down-regulation of phospho- ERK1/2 and
enhancement of the cytochrome c release.

34 16/12/14
Corydalis
* In another study, Gao et al. (2008) found that the yanhusuo
extract inhibited the migration and invasion of MDA-MB-231
cells in vitro. In addition, the yanhusuo extract inhibited the
mRNA expression and activity of MMP-9.
* The anti-cancer metastasis eect of yanhusuo involved the
activation of p38 and inhibition of ERK1/2 and SAPK/JNK
mitogen-activated protein kinase (MAPK) signalling.
* Nine alkaloids from the dichloromethane extract of C.
yanhusuo and were tested for their aromatase binding
activities. The results showed that the quaternary
protoberberine alkaloids and the tertiary protoberberine
alkaloids had aromatase binding activities (Shi et al., 2010)
drdweber@panaxea.com 35 16/12/14
Ganoderma lucidum
* Ganoderma lucidum (ling zhi) suppresses phosphorylation of
Akt on Ser473 and downregulates the expression of Akt,
which results in the inhibition of NF-kappaB activity in MDA-
MB-231 cells.
* The biological eect of Ganoderma lucidum was
demonstrated by cell cycle arrest at G0/G1, which was the
result of the downregulation of expression of NF-kappaB-
regulated cyclin D1, followed by the inhibition of cdk4.
* Ganoderma lucidum suppresses the invasive behaviour of
breast cancer by inhibiting the growth of MDA-MB-231 breast
cancer (Jiang et al., 2004).

drdweber@panaxea.com 36 16/12/14
Strobilanthes crispus
* Selected sub-fractions of the dichloromethane extract of S.
crispus induced death of MCF-7 (breast), MDA-MB-231 (TNBC),
PC-3 (prostate) and DU-145 (prostate) cells (Yaacob et al., 2010).
* The combined Strobilanthes crispus leaves (SCS) and tamoxifen
treatment displayed strong synergistic inhibition of MCF-7 and
MDA-MB-231 cell growth at low doses of the anti-oestrogen.
SCS further promoted the tamoxifen-induced apoptosis that
was associated with modulation of mitochondrial membrane
potential and activation of caspase-8 and caspase-9, suggesting
the involvement of intrinsic and extrinsic signalling pathways
(Yaacob et al., 2014).

drdweber@panaxea.com 37 16/12/14
Shiraia bambusicola
* 11,11'-dideoxy-verticillin, a compound of the novel
epidithiodioxopiprazine structural class, is isolated from the
traditional Chinese medicinal herb Shiraia bambusicola (zhu
huang) and has potent tyrosine kinase-inhibitory and anti-
tumour activities.
* 11,11'-dideoxy-verticillin signicantly inhibited the activities of
epidermal growth factor receptor (EGFR), vascular endothelial
growth factor receptor-1/fms-like tyrosine kinase-1 (VEGFR-1/
Flt-1) and human epidermal growth factor receptor-2 (HER2/
ErbB-2), with relative specicity on EGFR and VEGFR-1. MB-
MB-468 cells exhibited signicant apoptotic morphological
changes (Zhang et al., 2005).
drdweber@panaxea.com 38 16/12/14
TNBC
* 50 cases of postoperative TNBC were given JLBSHJ formula
orally, the control group consisting 50 cases took
chemotherapy. 5-year observation was followed.
* The survival rate was in the control group 80%, the treated
group 94%; the life quality improving rate: the control group
68%, the treated group 90%; local recurrence rate: the control
group 36%, the treated group 20%, remote metastasis rate:
the control group 24%, the treated group 6%.
* Total recurrence rate: the control group 76%, treated group
26%; bone marrow inhibition rate: the control group 90%, the
treated group 10%

drdweber@panaxea.com 39 16/12/14
TNBC
* Cellular immune function: CD4/CD8 ratio in the control group
was (1.100.18), and the treated group was (1.470.30)
(P<0.05); NK cell activity in the control group was
(19.134.86), and(30.166.06) in the treated group (P<0.05).
* Compared with chemotherapy regimen, the treatment of
JLBSHJ on postoperative TNBC could prolong the survival
rate of the patients, improve their life quality, increase
cellular immune function, lower side and toxic eect, and
lower remote metastasis rate (Hu Bei Zhong Yi Za Zhi. 2010,
32(6): 16-17)

drdweber@panaxea.com 40 16/12/14
Ji Li Bu Shen He Ji Formula
* Semen Astragali complanati * Fructus Lycii (gou qi) 15g
(sha yuan zi or tong ji li) 30g * Radix Glycyrrhizae Uralensis
* Radix Rehmanniae Praeparata (zhi gan cao) 6g
Glutinosae Praeparata (shu * Cortex Eucommiae Ulmoidis
di) 20g (du zhong) 15g
* Radix Dioscoreae * Cortex Cinnamomi Cassiae
Oppositae (shan yao) 15g (rou gui) 3g
* Fructus Corni Ocinalis * Radix Aconiti Carmichaeli
(shan zhu yu) 10g Praeparata (fu zi) 15g

drdweber@panaxea.com 41 16/12/14
TNBC
* 40 cases of TNBC were averagely divided into 2 groups
according to the patients choice, the treated group was
given oral administration of herbs and had regular
examination, the control group only had regular examination.
* After a few years of clinical research, its found that TCM had
positive therapeutic eect on TNBC, theres signicant
dierence compared with the control group.
* TCM treatment on TNBC eectively controlled the recurrence
and metastasis of these patients, prolonged the survival time
and improved the life quality (Zhong Guo wu Zhen Xue Za Zhi.
2010, 10(19): 4566-4567).

drdweber@panaxea.com 42 16/12/14
Formula 2
* Rhizoma Iphigeniae Indicae * Rhizoma Pinelliae Ternatae
(shan ci gu) 30g (ban xia) 12g
* Herba Solanum Nigrum * Spica Prunellae Vulgaris (xia
(long kui) 30g ku cao) 15g
* Radix Bupleuri (chai hu) 15g * Concha Ostreae (mu li) 30g
* Tuber Curcumae (yu jin) 15g * Radix Glycyrrhizae Uralensis
* Rhizoma Sparganii (gan cao) 10g
Stoloniferi (san leng) 15g * Radix Angelicae Sinensis
* Rhizoma Curcumae Ezhu (e (dang gui) 15g
zhu) 15g

drdweber@panaxea.com 43 16/12/14
Oestrogen Receptor /
Progesterone Receptor
Positive

drdweber@panaxea.com 44 16/12/14
Oestrogen Metabolism
* The liver is a site for biosynthesis of oestrogens but it is also
the main site for further biotransformation of them. Once the
oestrogens are synthesised by aromatase in peripheral
tissues including the liver, they will be released to the
circulation.
* Oestrone is in equilibrium with oestradiol and 17-b-
hydroxysteroid dehydrogenase (17bHSD) in this respect. The
oestrogens are taken up by the liver where they will be bio-
transformed further in to dierent metabolites. The major
oxidative routes of oestrone and oestradiol are 2- and 4-
hydroxylation by cytochrome P450 (CYP) 2B1, 1A and 3A.
Other minor oxidative pathways are also identied.
drdweber@panaxea.com 45 16/12/14
Oestrogen Metabolism
* Oxidative metabolism of the oestrogens oestrone (E1) and
oestradiol (E2) is the critical event in the initiation of cancer
by oestrogens. E1 and E2 are oxidised by cytochrome P450
(CYP) to the catechol oestrogens 2-OHE1(E2) and 4-OHE1(E2)
and then to the catechol oestrogen quinones, which react
with DNA to form oestrogen-DNA adducts.
* Oestrogen metabolism becomes unbalanced when
expression of the activating enzymes CYP19 (aromatase) and
CYP1B1 is higher and expression of the protective enzymes
catechol-O-methyltransferase and quinone reductase is lower
(Rogan & Cavalieri, 2011).

drdweber@panaxea.com 46 16/12/14
Oestrogen Metabolism
* The 2- and 4-hydroxy derivatives (and other metabolites) will
be further converted to 2- and 4-methoxy metabolites by
catechol-O-methyltransferase (COMT). While the
hydroxylated metabolites appear to result in DNA damage
and contribute to the tumorigenic eect of oestrogen, the
methoxy-derivatives appear to exhibit benecial
cardiovascular eects.
* Oestrone and oestradiol and their metabolites undergo
sulfation by sulfotransferases (SULTs) and glucuronidation by
glucoronyltransferases (UGTs). Oestrone and oestradiol
sulfates could be deconjugated by sulfatases (STs).

drdweber@panaxea.com 47 16/12/14
Oestrogen Metabolites
* 16 alpha-OHE1 is a powerful metabolite that stimulates target
tissues. Levels can rise in response to obesity, alcohol
consumption, and toxic exposure. High levels of this potent
metabolite are linked to increased risk and poorer prognosis
in conditions linked to oestrogen excess such as breast
cancer and lupus.
* 4-hydroxyestrone (4-OHE1) may react negatively with
damaged DNA. It plays an important role in breast
carcinogenesis because of its ability to induce DNA
depurination independent of ER binding. 4OHE1
concentration, may have confounded results for oestrogen
metabolite ratio (EMR).
48 16/12/14
Metabolic Pathways
* The two main pathways for metabolising oestrogen are via
16alpha-hydroxylation and 2-hydroxylation. The 16-OHE1
metabolites are biologically active; the 2-OHE1 metabolites
are not. It is suggested that women who metabolise a larger
proportion of their endogenous oestrogen via the 16alpha-
hydroxy pathway may be at signicantly elevated risk of
breast cancer compared with women who metabolise
proportionally more oestrogen via the 2-hydroxy pathway.
* Studies by Ursin et al., (1997) and Cauley et al., (2003) do not
support the hypothesis that the ratio of the two
hydroxylation metabolites (2-OHE1/16alpha-OHE1) is an
important risk factor for breast cancer
drdweber@panaxea.com 49 16/12/14
Metabolic Pathways
* There are indications that additional factors such as certain
genetic polymorphisms and excessive oxidative stress are
necessary to inuence the synthesis of intermediate
aggressive metabolites, which may already have gene toxicity
at low concentrations and can destruct DNA structures and/
or have the potency to inuence carcinogenesis by intensive
proliferative actions (Mueck & Seeger, 2007).
* It remains doubtful whether physiological oestradiol per se
can be causally carcinogenic by proliferative processes
(International Menopause Society, 2009).

drdweber@panaxea.com 50 16/12/14
Oestrogen Metabolism
Progesterone

DHEA-S
Androstenedione
SHBG
Testosterone

Oestrone
Oestrodiol (E2)
Sulphate
Oestrone (E1)

2-OHE1 4-OHE1 16-OHE1

2-MeOE2 4-MeOE2 Oestriol (E3)

Carcinogenic metabolites are shown in red and anti-carcinogenic or neutral metabolites are shown in green.
Genes Evaluated by EstroGene Test
* Phase I Detoxication
* CYP1A1 Oestrone to 2-OH Oestrone (E1)
* CYP1B1 Oestrone to 4-OH E1
* CYP3A4 Oestrone to 16-alpha OH E1
* Phase II Detoxication
* COMT Methylation of 2-OH and 4-OH E1
* GST Quinones to Glutathione Conjugates
* MnSOD Free Radicals Quenced

https://www.estrogengenetest.com/
Enter: MPI license number for Practitioner discount
Botanicals & Oestrogen Metabolism
* Panax notoginseng signicantly increased mRNA expressions
of GSTm1 and CYP1A1 in the 2 gkg-1 and 4 gkg-1 bw/d
treatment groups, respectively, but P. notoginseng had a
inhibitory tendency on mRNA expressions of CYP1B1 and
signicantly inhibited the expressions of CYP2B1 (Yang et al.,
2009).
* Rhizoma curcumae extract could increase and induce the
enzyme activity and mRNA expression of CYP3A4 (Shao et al.,
2008).
* Flos Chrysanthemi, Fructus Lycii, Radix et Rhizoma Salviae
Miltiorrhizae, Fructus Crataegi, Flos Lonicerae Japonicae,
Rhizoma Dioscoreae are inducers of CYP3A4 (Xu et al., 2011).
drdweber@panaxea.com 53 16/12/14
Who Should be Tested
to Reduce Breast Cancer Risk?
* Womens Health Initiative study rst published in 2002 conclusively
demonstrated the 2.5 increased breast cancer risk from cumulative oestrogen
exposure. How can we pinpoint which women are more at risk?

* By a genetic assessment of how a woman metabolizes oestrogen. Women with 3
or more genetic mutations have 2.5 to 13x greater breast cancer risk.

All women should be tested to know if they possess the risk
* Practically speaking, testing should take place when contemplating exogenous
oestrogen use or for those with ER+ breast cancer history

Hormone ER-Positive
Oral In Vitro Replacement Bio-identical ER-Positive Breast Cancer
Contraceptives Fertilization Hormones Breast Cancer Family History
Therapy
Testing
* It is appropriate to test every woman once in their lifetime,
perhaps as part of an initial gynecological screening.
Practically speaking, the Oestrogen Gene Tests should be
ordered when before prescribing exogenous oestrogens. For
example, prior to starting oral contraception, hormone
replacement therapy or bio-identical hormones, and
especially IVF. All women with current or previous exposure
should be tested.
* Certainly, women with a history of oestrogen receptor-
positive breast cancer need to know or verify that they have
multiple snps and add oestrogen metabolism improvement
techniques to their standard breast cancer treatment.
drdweber@panaxea.com 55 16/12/14
Er vs ER
* The oestrogen receptor (ER) isoform known as ER has
become the focus of intense investigation as a potential drug
target. The existence of clear-cut dierences in ER and ER
expression suggests that tissues could be dierentially
targeted with ligands selective for either isoform (Couse et
al., 1997; Enmark et al., 1997).
* In particular, the fact that ER is widely expressed but not
the primary oestrogen receptor in, for example, the uterus
(Harris, Katzenellenbogen, & Katzenellenbogen, 2002) opens
up the possibility of targeting other tissues while avoiding
certain classical oestrogenic eects.

drdweber@panaxea.com 56 16/12/14
Daidzein
* Charalambous, Pitta & Constantinou (2013) found that equol
(>50M) and 4-hydroxy-tamoxifen (4-OHT; >100 nM) both
signicantly reduced the breast cancer MCF-7 cell viability.
Daidzein and its metabolite S-(-)-equol showed the potential
of inhibiting the growth of mammary tumours. Daidzein or S-
(-)-equol could be used as a core structure to design new
drugs for breast cancer therapy. Our results indicate that
consumption of daidzein may protect against breast cancer
(Liu et al., 2012).
* Daidzein could induce breast cancer cell apoptosis through
the mitochondrial caspase-dependent cell death pathway (Jin
et al., 2010).
drdweber@panaxea.com 57 16/12/14
S-Equol
* The soy isoavone daidzin was isolated and shown to be a
precursor to equol (Axelson et al., 1982). It was also found
that the introduction of soy protein to the diet led to an
increased excretion of equol in some but not all adults
(Setchell et al., 1984).
* The nding of high concentrations of equol, a nonsteroidal
oestrogen; in the urine of adults consuming fermented soy
foods prompted the hypothesis that this nonsteroidal
oestrogen may be benecial in the prevention and treatment
of many hormone-dependent conditions.

drdweber@panaxea.com 58 16/12/14
Er vs ER
* Isoavone (genistein) consumption indicate the possible
contribution of ER-specic signalling in breast cancer
prevention. A selective oestrogen receptor modulator, which
works as an antagonist of ER and an agonist of ER, may be
a promising chemo-preventive treatment (Saji, Hirose, & Toi,
2005).
* ER works as counter partner of ER through inhibition of
the transactivating function of ER by heterodimerization,
distinct regulation on several specic promoters by ER or
ER, and ER-specic regulated genes which are probably
related to its anti-proliferative properties

drdweber@panaxea.com 59 16/12/14
Genistein
* Genistein signicantly decreased both gene and protein
expression of Rho GTPases (Rho, Rac, and Cdc42) and the
downstream eector of Rac and Cdc42, PAK1, are signicant
for understanding the mechanism by which genistein inhibits
cancer cell invasion, and may reduce breast cancer progression
via transcriptional regulation (Vadlamudi et al., 2004; Vega &
Ridley, 2008).
* Genistein is a potent inhibitor of the growth of the human
breast carcinoma cell lines, MDA-468 (oestrogen receptor
negative), and MCF-7 and MCF-7-D-40 (oestrogen receptor
positive). The presence of the oestrogen receptor is not
required for the isoavones to inhibit tumour cell growth
(Peterson & Barnes, 1991) 60 16/12/14
Genistein
* Results also suggest that genistein could be useful as a
chemotherapeutic agent in premenopausal women with
breast cancer of the ER-negative and ER-positive type
(Rajah et al., 2009).
* ER has been postulated to play a role in modulating ER-
mediated cell proliferation, genistein and quercetin may be
agonists for both receptor types and the ratio of ER to
ER is known to vary between tissues and results point at the
importance of the cellular ER/ER ratio for the ultimate
eect of phytoestrogens on cell proliferation (Sotoca et al.,
2008).

drdweber@panaxea.com 61 16/12/14
See
* Daniel Weber. Phytoestrogens and Cancer. Cancer Strategies
Journal Winter 2014

drdweber@panaxea.com 62 16/12/14
Er vs ER
* Selective ER agonists can stimulate either ER- or ER- and
induce tissue-specic oestrogen-like eects. MF-101 is derived
from 22 herbs that are traditionally used in Chinese medicine
for the treatment of menopausal symptoms.
* Studies with the MF-101-isolated active compounds, liquiritigen
and chalcone, demonstrated selectivity for ER-, with no
induction of proliferative events. MF-101 did not promote the
growth of breast cancer cells or stimulate uterine tissue
(Stovall & Pinkerton, 2009).
* MF101, a selective oestrogen receptor agonist is a safe and
eective for treating menopausal hormone therapy and
nighttime awakenings (Leitman & Christians, 2012).
drdweber@panaxea.com 63 16/12/14
MF101
* Scutellaria barbata (Ban Zhi * Pueraria montana (Ge Gen)
Lian) * Glycine max (Hei Dou)
* Atractylodes macrocephala * Achyranthes bidentata (Huai
(Bai Zhu) Niu Xi)
* Rheum palmatum (Da Huang) * Huang Qi (Astragalus
* Wolporia extensa (Fu Ling) mongholicus)
* Triticum aestivum (Fu Xiao * Lian Zi Xin (Nelumbo nucifera)
Mai) * Paeonia suruticosa (Mu Dan
* Glycyrrhiza uralensis (Gan Pi)
Cao)

64 16/12/14
MF101
* Mu Li (Crassostrea gigas) * Tian Men Dong (Asparagus
* Nu Zhen Zi (Ligustrum cochinchinensis)
lucidum) * Epimedium spp. (Yin Yang Huo)
* Sheng Di Huang * Anemarrhena asphodeloides
(Rehmannia glutinosa) (Zhi Mu)
* Shan Dou Gen (Sophora * Ze Xie (Alisma plantago-
tonkinensis) aquatica)
* Shan Zhu Yu (Cornus * Chalcone
ocinalis) * Liquiritigenin
* Suan Zao Ren (Ziziphus
jujuba)
65 16/12/14
Chalcone
* Hsu et al., (2006) examined (1,3-diphenyl-2-propenone) for its
eect on proliferation in human breast cancer cell lines,
MCF-7 and MDA-MB-231. The results showed that chalcone
inhibited the proliferation of MCF-7 and MDA-MB-231 by
inducing apoptosis and blocking cell cycle progression in the
G2/M phase.
* Chalcone extracted from Taraxacum ocinale also triggered
the mitochondrial apoptotic signalling by increasing the
amount of Bax and Bak and reducing the level of Bcl-2 and
Bcl-XL, and subsequently activated caspase-9 in MCF-7 and
MDA-MB-231 cells.

drdweber@panaxea.com 66 16/12/14
Liquiritigenin (LQ)
* LQ separated from Glycyrrhiza radix, possesses anti-
inammatory, anti-hyperlipidaemic, and anti-allergic eects.
The expression of cleaved PARP, the hall-marker of
apoptosis, was enhanced by LQ. LQ treatment also resulted
in a reduction of the expressions of B-cell lymphoma 2 (Bcl-2)
and B-cell lymphoma-extra large (Bcl-xL), and an increase of
the phosphorylation of c-Jun N-terminal kinases (JNK) and
P38.
* LQ suppressed the activation of extracellular signalling-
regulated kinase (ERKs) and reduced the translocation of
phosphor-ERKs from cytoplasm to nucleus (Wang et al, 2014).

drdweber@panaxea.com 67 16/12/14
ER+/PR+
* Ganoderma lucidum and Scutellaria baicalensis, have been
reported to suppress ER expression in vitro (Jiang, Slivova &
Sliva, 2006; Chung et al., 2008).
* Cryptotanshinone has been recently evaluated for its anti-
cancer activity and is a potent stimulator of ER stress, leading
to apoptosis in many cancer cell lines including MCF7 breast
carcinoma.
* Cryptotanshinone also evidenced sensitising eects to a broad
range of anti-cancer agents including Fas/Apo-1, TNF-,
cisplatin, etoposide or 5-FU through inducing ER stress,
highlighting the therapeutic potential in the treatment of
breast cancer (Park et al., 2012).
drdweber@panaxea.com 68 16/12/14
ER+/PR+
* Tanshinone IIA is a widely used Chinese herbal medicine
isolated from Danshen (Salvia miltiorrhiza) that may have anti-
inammatory and anti-oxidant properties, as well as cytotoxic
activities against multiple human cancer cell lines.
* Tanshinone IIA might have potential anti-cancer activity that is
stronger than tamoxifen in both ER-positive and ER-negative
breast cancers. This function could be attributed in part to its
inhibition of proliferation and apoptosis induction in cancer
cells via the downregulation of multiple genes involved in cell
cycle regulation, cell proliferation, apoptosis and DNA
synthesis (Lu et al., 2009).

drdweber@panaxea.com 69 16/12/14
Panaxea Tanshins
* Salvia Miltiorrhiza (contains * Clears Heat and eliminates
standardised extracts toxins, activates blood
Tanshinone IIA and circulation, dispels stasis,
Cryptotanshinone) generates body uids, dispels
* Cytotoxic wind and opens channels and
* Apoptoxic collaterals.
* Inhibits angiogenesis

drdweber@panaxea.com 70 16/12/14
ER+/PR+
* DNA microarray technology has been used to understand the
molecular mechanism underlying the anti-cancer eect of
berberine carcinogenesis in two human breast cancer cell
lines, the ER-positive MCF-7 and ER-negative MDA-MB-231 cells;
specically, whether it aects the expression of cancer-related
genes.
* Treatment of the cancer cells with berberine markedly
inhibited their proliferation in a dose- and time-dependent
manner. The growth-inhibitory eect was much more
profound in MCF-7 cell line than that in MDA-MB-231 cells
(Kang et al., 2005).

drdweber@panaxea.com 71 16/12/14
Metalloestrogens
* Aluminium chloride or aluminium chlorhydrate can interfere
with the function of oestrogen receptors of MCF7 human
breast cancer cells both in terms of ligand binding and in
terms of oestrogen-regulated reporter gene expression.
* This adds aluminium to the increasing list of metals capable of
interfering with oestrogen action and termed
metalloestrogens (Darbre, 2005).
* Other metalloestrogens are arsenite, nitrite, selenite, and
vanadate while the bivalent cations include metals such as
cadmium, calcium, cobalt, copper, nickel, chromium, lead,
mercury, and tin (Byrne et al., 2013).

drdweber@panaxea.com 72 16/12/14
Emodin & Aloe-emodin
* Huang et al., (2013) reported results that indicated both
emodin and aloe-emodin are capable of inhibiting breast
cancer cell proliferation by down-regulating ER protein
levels, thereby suppressing ER transcriptional activation.
Furthermore, aloe-emodin treatment led to the dissociation
of heat shock protein 90 (HSP90) and ER and increased ER
ubiquitination.
* Data demonstrate that emodin and aloe-emodin specically
suppress breast cancer cell proliferation by targeting ER
protein stability through distinct mechanisms.

drdweber@panaxea.com 73 16/12/14
Emodin & Aloe-emodin
* Huang, Chen, Shi (2008) focused on the eect of emodin in
human breast cancer BCap-37 cells and further understand
the underlying molecular mechanism in treating breast
cancer.
* The results of the study further showed that Bcl-2 level
decreased, while Bax and cytosolic cytochrome c levels in
sample cells increased after the emodin treatment. The
decline in the Bcl-2/Bax ratio and the increase of cytosolic
cytochrome c concentration were consistent with the
increase of the apoptotic ratio.

drdweber@panaxea.com 74 16/12/14
Panaxea Emodin
* Panaxea Emodin Complex * Recent research has suggested
extracted from Rheum that plant polyphenols such as
Palmatum (da huang) contains emodin may be used to
Emodin (1, 3, 8 - trihydroxy - 6 sensitise tumour cells to
methylanthraquinone) and chemotherapeutic agents and
Glycyrrhiza Uralensis extract radiation therapy by inhibiting
(gan cao) pathways that lead to
treatment resistance. Such
agents have also been found to
be protective from therapy-
associated toxicities (Garg et
al., 2005)
drdweber@panaxea.com 75 16/12/14
Panaxea D:Fend
* 350mg Daidzein/Daidzin * MS-20 demonstrated its ability
* 470 mg Genistein/Genistin to restore chemotherapy-
* 110 mg Glycitein/Glycitin induced immunosuppression
and improve quality of life (Chi
Taken with
et al., 2014).
* MicrSoy-20 (MS-20) * Fermented soy product (FSP)
or was most ecient in tumour
* Haelan 951 (Bachg & containment, possibly due to a
Haselhorst, 2007) positive modulation of the
Or immune system (Kinouchi et al.,
* FSP 2012)

drdweber@panaxea.com 76 16/12/14
FSP
* FSP caused apoptotic cell death in MCF-7 cells. FSP induced
generation of reactive oxygen species (ROS) indicating that
the ROS production probably was the cause of this apoptotic
cell death. This study suggests that FSP retards tumour
growth in vivo and can trigger apoptosis in vitro (Chang et al.,
2002).
* Daily ingestion of the probiotic soy product may contribute to
a benecial balance of the faecal microbiota and this
modulation is associated with an improved cholesterol prole
(Cavallini et al., 2011).

drdweber@panaxea.com 77 16/12/14
Haelan
* Haelan helps repair DNA damage, thereby allowing
chemotherapy to be more eective.
* Haelan is anti-angiogenic, and pro-apoptotic.
* Haelan may disrupt signals of epidermal Growth Factor
Receptors; possibly blocking the signals altogether.
* Haelan may cause a reactivation of the P53 tumour
suppressor protein for these specic patients
* Haelan is known to shut o the Nuclear Factor Kappa Beta
(NF-Kb) mutation capability completely.

drdweber@panaxea.com 78 16/12/14
D:FEND
* D:FEND normalises cell function and contains herbal
phytoestrogens. Phytoestrogens are plant-derived
compounds found in a wide variety of foods, most notably
soy. A litany of health benets is frequently attributed to
phytoestrogens. D:Fend induces apoptosis via the
mitochondrial pathway (Stark & Madar, 2002).
* It is involved in cell cycle arrest, antiangiogenic potential,
antimetastatic potential and in enhancing radiotherapy
treatment. In various cancer models phytoestrogens
signicantly inhibit tumour growth, invasion and metastasis
(Virk-Baker et al., 2010; Vitale et al., 2013)

drdweber@panaxea.com 79 16/12/14
Oldenlandia diusa (OD)
* Gu et al., (2012) observed that extracts bai hua she she cao
strongly inhibited anchorage-dependent and -independent
cell growth and induced apoptosis in oestrogen receptor
alpha (ER)-positive breast cancer cells, whereas
proliferation and apoptotic responses of MCF-10A normal
breast epithelial cells were unaected.
* Mechanistically, OD extracts enhance the tumour suppressor
p53 expression as a result of an increased binding of ER/Sp1
complex to the p53 promoter region.
* OD exerts antiproliferative and apoptotic eects selectively in
ER-positive breast cancer cells.

drdweber@panaxea.com 80 16/12/14
Resveratrol & Ursolic Acid
* Resveratrol, a phytoalexin, and ursolic acid, a pentacyclic
triterpenoid, are two bioactive compounds that have anti-
inammatory actions, induce apoptosis and have anti-cancer
activities by targeting signal pathways.
* Ursolic acid treatments of MCF-7 breast cancer cells induced
apoptosis through internal mitochondrial pathways (Kassi et
al., 2009). This nding is further substantiated when on
treating MDA-MB-231 cells with ursolic acid an induction of
mitochondrial mediated cancer cell apoptosis was observed
(Kim et al., 2011). Ursolic acid was found to release
cytochrome C from the mitochondria to the cytosol, to up-
regulate the Bax protein as well as a down-regulate Bcl-2.
drdweber@panaxea.com 81 16/12/14
Ursolic Acid
* UA was found to inhibit the proliferation of MCF-7 cells in a
concentration and time-dependent manner. After treatment,
UA-induced apoptosis was accompanied by a signicant
decrease in CyclinD1/CDK4 expression, which can be
regulated by FoxM1. Previous studies demonstrated that
FoxM1 orchestrates the transcription of genes that are
essential for cell cycle progression and cell proliferation
(Wang, Ren, Xi, 2012).
* UA-induced apoptosis (53 M), the PARP cleavage, and
decreased Bcl-2 protein (53 M) to support the notion that
UA induces apoptosis through the intrinsic mitochondrial
pathway (Kassi et al., 2009).
drdweber@panaxea.com 82 16/12/14
Panaxea Ursolic Acid
* We use only pharmaceutical grade UA that is micronised for
greater bio-availability. Most UA that is commercially
available is either industrial or cosmetic grade.

drdweber@panaxea.com 83 16/12/14
Panaxea antiEST
* The actions of unopposed oestrogen or oestrogen in the face
of progesterone (P) resistance can promote various
gynaecologic disorders, including endometriosis, endometrial
hyperplasia, and cancer.
* Collins et al., (2009) investigated the botanical herb Prunella
vulgaris (PV) and found that extracts of this plant have anti-
oestrogenic activities.
* Methanol extract of PV exhibits signicant anti-oestrogenic
properties, both in vitro and in vivo. This activity is likely due
to the ability of PV-activated aryl hydrocarbon receptor (AHR)
to interfere with oestrogen

drdweber@panaxea.com 84 16/12/14
HER2/neu

drdweber@panaxea.com 85 16/12/14
HER-2/neu
* HER2 is a member of the epidermal growth factor receptor
(EGFR/ERBB) family. Amplication or overexpression of this
oncogene has been shown to play an important role in the
development and progression of certain aggressive types of
breast cancer.
* In recent years the protein has become an important
biomarker and target of therapy for approximately 30% of
breast cancer patients.
* It is strongly associated with increased disease recurrence
and a poor prognosis. Over-expression is also known to occur
in ovarian, stomach, and aggressive forms of uterine cancer,
such as uterine serous endometrial carcinoma.
drdweber@panaxea.com 86 16/12/14
HER-2/neu
* The amplication and overexpression of the HER-2/neu proto-
oncogene, which encodes the tyrosine kinase receptor
p185neu, have been observed frequently in tumours from
human breast cancer patients and are correlated with poor
prognosis.
* Results indicate that emodin inhibits HER-2/neu tyrosine
kinase activity and preferentially suppresses growth and
induces dierentiation of HER-2/neu-overexpressing cancer
cells (Zhang et al., 1995; Zhang et al., 1999).

drdweber@panaxea.com 87 16/12/14
P53 & Ki67
* The Ki67 marker and P53 protein are important factors in the
HER-2/neu breast cancer patients with emphasis on
therapeutic agents. Results of the study suggested that the
p53 protein and Ki67 marker are important factors in the
prognosis of metastasis and survival rate in patients with
breast cancer.
* It is important that patients of Immunohistochemistry (IHC
2+) with Ki67 positive or p53 positive get treated with
adjuvant therapy (Payandeh et al., 2014).

drdweber@panaxea.com 88 16/12/14
P53 & Ki67
* Scutellaria baicalensis increased expression of p53 in the cancer
cells of key proteins related to the enhancement of apoptosis is
observed (Gao et al., 2011). Similarly, Gleditsia sinensis thorns
are used as a medicinal herb, which shows a decrease in cell
growth and an increase in cell cycle arrest during the G2/M-
phase. The arrest is correlated with increased p53 levels and
down-regulation of cyclinB1 (Lee et al., 2010).
* Ki-67, a nuclear antigen, is widely considered as a marker of
cellular proliferation. With Radix Sophorae Tonkinesis and
Rhizoma Curcumae expression of Ki-67 antigen was signicantly
dierent in the normal, hyperplastic and mild dysplastic cancers
(Zhou & Zhang, 2005).
89 16/12/14
HER-2/neu
* After surgery selected HER2/neu transgenic spontaneous
breast tumour model mice were randomly divided them into
control group, traditional Chinese medicine group (RSR
group), western medicine group (Trastuzumab group), and
the combination group (RSR and Trastuzumab group) and
treated with corresponding medicine for 4 month.
* Ruai Shuhou Recipe can inhibit recurrent tumour volume
in transgenic mice after operation, block the HER2-mediated
p38 MAPK and PI3K-Akt signal pathways, inhibit tumour cell
proliferation and promote tumour cell apoptosis (Shao et al.,
2013).

drdweber@panaxea.com 90 16/12/14
Ru Ai Shu Hou Fang
* Rhizoma Alocasiae * Radix Adenophorae (nan sha
Macrorrhizae (she liu gu) shen) 15g
(decocted rst) 60g * Rhizoma Curcumae Ezhu (e
* Radix Astragali (huang qi) zhu) 30gm
30gm * Herba Salviae Chinensis (shi
* Radix Codonopsis (dang jian chuan) 30gm
shen) 12gm * Radix Ledebouriellae
* Radix Atractylodes (bai zhu) Divaricatae (feng fang) 12gm
10gm * Cornu Cervi gel (lu jiao pian)
* Herba Epimedii (yin yang 12gm
huo) 15gm
drdweber@panaxea.com 91 16/12/14
Ru Ai Shu Hou Fang
* Herba Sargassii (hai zao) 30gm * Os Draconis calcined (duan
* Herba Cistanches (rou cong long gu) 30gm
rong) 12gm * Radix Cynanchi Paniculati (xu
* Radix Achyranthis Bidentatae chang qing) 30gm
(huai niu xi) 30gm * Gummi Olibanum (ru xiang)
* Fructus Psoraleae Corylifoliae 10gm
(bu gu zhi) 30gm * Herba Scutellariae Barbatae
* Concha Ostreae calcined (duan (ban zhi lian) 30gm
mu li) 30gm * Rhizoma Corydalis (yan hu
* Rhizoma Curcumae Longae suo) 30gm
(jiang huang) 30gm * Scolopendra Subspinipes (wu
* Poria Cocos (fu ling) 12gm 92 gong) 3gm 16/12/14
HER-2/neu
* Honokiol, an active component isolated and puried from
Chinese traditional herb magnolia, was demonstrated to
inhibit growth and induce apoptosis of dierent cancer cell
lines such as human leukaemia, colon, and lung cancer cell
lines; to attenuate the angiogenic activities of human
endothelial cells in vitro; and to eciently suppress the
growth of angiosarcoma in nude mice.
* Inhibition of HER-2 signalling by specic human epidermal
growth receptor 1/HER-2 (EGFR/HER-2) kinase inhibitor
lapatinib synergistically enhanced the anti-cancer eects of
honokiol in HER-2 over-expressed breast cancer cells (Liu et
al., 2008)
drdweber@panaxea.com 93 16/12/14
HER-2/neu
* The anthocyanins cyanidin-3-glucoside (C3G) and
peonidin-3-glucoside from Hibiscus sabdaria have been
identied as potential drugs for the therapy of HER2-positive
breast cancer. They have been used as supplements in targeted
therapeutics and chemotherapeutics in Asia.
* The combination treatments induced apoptosis, inhibited cell
growth and aected HER2 and its downstream signalling
pathway in MDA-MB-453, BT474 and HCC1569 cells, the eects
were synergistic. The combination of 3CG and trastuzumab
(Trast) inhibited tumour growth in an in vivo xenograft model.
The data from the present study suggested that C3G exhibits
potent antitumour activity when combined with Trast (Liu et al.,
2014) 94 16/12/14
HER-2/neu
* Tyrosine kinase inhibitors such as emodin can target the HER2/
neu oncogenic activity. Emodin treatment inhibits HER2/neu
tyrosine kinase activity and preferentially suppresses the
transformation of HER2/neu-overexpressing breast cancer cells.
* Emodin also sensitises HER2/neu-overexpressing cancer cells to
chemotherapeutic agents, including cisplatin, doxorubicin,
etoposide, and paclitaxel. Alternatively, HER2/neu
overexpression can be repressed by attenuating the promoter
activity of the HER2/neu gene (Wang et al., 2001).

drdweber@panaxea.com 95 16/12/14
HER-2/neu
* The combination of emodin AMAD treatment and siRNA against
Her2 synergistically inhibited proliferation and induced
apoptosis. Taken together, these data suggest that blockade of
Her2/neu binding to Hsp90 and following proteasomal
degradation of Her2/neu were involved in emodin azide methyl
anthraquinone derivative (AMAD)-induced apoptosis in Her2/
neu-overexpressing cancer cells (Yan et al., 2011).

drdweber@panaxea.com 96 16/12/14
HER-2/neu
* As an anti-cancer agent, emodin has been shown to suppress the
growth of various tumour cell lines including hepatocellular
carcinoma, pancreatic, breast, colorectal, leukaemia, and lung
cancers.
* Emodin is a pleiotropic molecule capable of interacting with
several major molecular targets including NF-B, casein kinase II,
HER2/neu, HIF-1, AKT/mTOR, STAT3, CXCR4, topoisomerase II,
p53, p21, and androgen receptors which are involved in
inammation and cancer.

drdweber@panaxea.com 97 16/12/14
HER-2/neu
* Apigenin exhibited potent growth-inhibitory activity in HER2/
neu-overexpressing breast cancer cells. Apigenin-induced
cellular eects result from loss of HER2/neu and HER3
expression with subsequent inactivation of PI3K and autologous
tumour killing (ATK) pathways in cells that are dependent on
this pathway for cell proliferation.
* This implies that the inhibition of the HER2/HER3 heterodimer
function provided an especially eective strategy for blocking
the HER2/neu-mediated transformation of breast cancer cells.
* The degradation of mature HER2/neu involves polyubiquitination
of HER2/neu and subsequent hydrolysis by the proteasome (Way
et al., 2005).
drdweber@panaxea.com 98 16/12/14
HER-2/neu
* Melatonin exhibits anti-inammatory and anticancer eects and
could be a chemopreventive and chemotherapeutic agent in
human Her-2 positive MDA-MB-361 breast cancer cells.
Melatonin markedly inhibited phosphorylation of PI3K, Akt,
PRAS40, and GSK-3 proteins, thereby inactivating the PI3K/Akt
signalling pathway.
* It induces Apaf-1 expression, triggered cytochrome C release,
and stimulated caspase-3 and caspase-9 activities and cleavage,
leading to an activation of the Apaf-1-dependent apoptotic
pathway.
* It inhibits cell proliferation and induces apoptosis by
simultaneously suppressing the COX-2/PGE2, p300/NF-B, and
PI3K/Akt/signalling (Wang et al., 99
2012). 16/12/14
Other Pathways

Breast Cancer

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Bax and Bcl-2
* The balance between Bax and Bcl-2 in favour of the former.
The ratio of Bax to Bcl-2 is a useful index to evaluate tumour
apoptosis induced by Kuper cells. An experiment by Chen et
al., (2002) suggests that alteration of the ratio of Bax to Bcl-2
may result from increased levels of iNOS and TNF.
* The combined assessment of Bcl-2 and Bax protein
expression may be used to predict a clinical response to
chemoradiation therapy based on the Bax/Bcl-2 ratio
determined before therapy. The Ki-67 index may be a useful
predictor of this prognosis (Matsumoto et al., 2004).

drdweber@panaxea.com 101 16/12/14


SZKJT
* There are only a few mechanistic studies on the action of TCM
formulas as anticancer agents. One study was on San Zhong Kui
Jian Tang (SZKJT), a complex formula comprising 17 dierent
herbs, that is used for cancer therapy in China.
* SZKJT was found to induce the mitochondrial apoptotic
pathway by changing Bax/Bcl-2 ratios, cytochrome c release and
caspase-9 activation in two human breast cancer cell lines,
MCF-7 and MDA-MB-231 (Hsu et al., 2006).
* Mitochondrial oncoproteins, such as bcl-2 and bax, represent
both sensitive indicators of clinical outcome and potential
targets of novel pro-apoptotic molecules in order to circumvent
chemoresistance (Del Poeta et al., 2002).
drdweber@panaxea.com 102 16/12/14
SZKJT
* Thallus Eckloniae (kun bu) * Radix Scutellariae (huang qin)
* Cortex Phellodendri (huang * Radix Paeoniae Alba (bai shao)
bai) * Radix Puerariae (ge gen)
* Rhizoma Anemarrhenae (zhi * Radix Bupleuri (chai hu)
mu) * Extremitas Radix Angelicae
* Radix Platycodi (Jie Geng) Sinensis (dang gui wei)
* Rhizoma Sparganii (san leng) * Radix Gentianae (long dan cao)
* Rhizoma Curcuma (e zhu) * Radix Cimicifugae (sheng ma)
* Fructus Forsythiae (lian qiao) * Radix Trichosanthis (tian hua
* Rhizoma Coptidis (Huang Lian) fen)
* Radix Glycyrrhizae Preparata * Rhizoma Zingiberis (sheng jiang)
(zhi gan cao)
drdweber@panaxea.com 103 16/12/14
Leonurus japonicus (yi mu cao)
* Data suggest that leonurus aqueous & ethanol extract may
eectively inhibit the proliferation of breast cancer cells
through mechanisms of both cytotoxicity and cell cycle
arrest. The cellular eects of the extract are non-apoptotic
and ER independent on breast cancer cells.
* The 70% ethanol extract in vivo markedly suppressed the
development of uterine adenomyosis and mammary cancers,
while the aqueous extract was previously reported to have
anti-cancer activity in breast cancer cells with low potency
(Tao et al., 2009).

drdweber@panaxea.com 104 16/12/14


Shenqi Fuzheng Injection
* In regard to advanced breast cancer, the herbal preparation
Shenqi Fuzheng Injection (SFI), was demonstrated to
alleviate bone marrow inhibition and cellular immunity
suppression caused by chemotherapy, and to relieve clinical
symptoms, raise the quality of life and prolong survival time
compared to patients receiving only chemotherapy.
* The total short-term remission rate, the improvement rate of
clinical syndrome and quality of life was 50.0%, 70.0% and
76.7% in the treatment group, and 43.3%, 46.7% and 50.0% in
the control group, respectively, showing signicant
dierence between the two groups (all P < 0.05).

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Shenqi Fuzheng Injection
* The occurrence of adverse reaction in the treatment group was
lower than that in the control group (P < 0.05). The level of
CD3+ CD4+ and CD4+/CD8+ ratio increased (P < 0.05) and CD8+
decreased in the treatment group (P < 0.01), while they
showed insignicant change in the control group (Huang et al.,
2008).
* SFI can improve and regulate immune function of the patients
with local advanced breast cancer given the neoadjuvant
chemotherapy, and therefore it can enhance the curative
eect and reduce the side eect as well. An obvious rise of the
T-lymphocyte subgroup and NK cells was found in the study
group after the neoadjuvant chemotherapy, with a very
signicant dierence from the 106 controls (P < 0.01). 16/12/14
Shenqi Fuzheng Injection
* Shenqi Fuzheng is a newly developed injection concocted
from two kinds of Chinese medicinal herbs: Radix Astragali
(huang qi) and Radix Codonopsis (dang shen) (Yang & Xu,
2004; Lu & Lu, 2006).
* It was approved by the State Food and Drug Administration
of the Peoples Republic of China in 1999 primarily as an
antitumour injection to be manufactured and marketed in
China (Zhong, 2009).

drdweber@panaxea.com 107 16/12/14


MDR Breast Cancer
* Paris saponin VII (PS VII), a kind of saponin, from Trillium
tschonoskii (yan ling cao) dose dependently suppressed cell
viability as well as triggered apoptosis and modulated drug
resistance of MCF-7/ADR cells.
* Further results showed that PS VII treatment in MCF-7/ADR
cells led to increased TNFR1, TRAIL R1/DR4, TRAIL R2/DR5, and
FADD expression, and activation of PARP, caspase-8, and 3. In
parallel to the alterations, P-glycoprotein expression and
activity were also reduced.
* These ndings showed that PS VII might be an eective
tumouristatic agent for the treatment of MDR breast cancer
(Li et al., 2014).
drdweber@panaxea.com 108 16/12/14
Breast METS
* MDA-MB-231 cell line is a highly metastatic breast cancer cell line.
The results demonstrated by Kim et al., (2008) that treatment
with berberine inhibits growth in both MDA-MB-231 and MCF-7
cells. This partly occurs through the induction of apoptosis in
MDA-MB-231 cells, and through both cell cycle arrest and
induction of apoptosis in MCF-7 cells.
* Ursolic acid, a naturally occurring triterpenoid, has various
anticancer activities. In this study, Yeh, Wu & Yen (2010)
observed that ursolic acid exerted a dose- and time-dependent
inhibitory eect on the migration and invasion of highly
metastatic breast MDA-MB-231 cells at non-cytotoxic
concentrations.
drdweber@panaxea.com 109 16/12/14
Breast METS
* The eect of berberine on invasion, migration, metastasis, and
angiogenesis is mediated through the inhibition of focal adhesion
kinase (FAK), NF-B, urokinase-type plasminogen-activator (u-PA),
matrix metalloproteinase 2 (MMP-2), and matrix
metalloproteinase 9 (MMP-9) (Ho et al., 2009; Hamsa & Kuttan.
(2011)
* Reduction of Rho kinase-mediated Ezrin phosphorylation (Tang et
al., 2009); reduction of the expression of COX-2, prostaglandin E,
and prostaglandin E receptors (Singh et al., 2011)
* Down-regulation of hypoxia-inducible factor 1 (HIF-1), vascular
endothelial growth factor (VEGF) and pro-inammatory mediators
(Jie et al., 2011; Hamsa & Kuttan, 2012).
110 16/12/14
Breast METS
* Berberine also inhibits the growth of Anoikis-resistant MCF-7 and
MDA-MB-231 breast cancer cell lines by inducing cell-cycle arrest.
Anoikis, or detachment-induced apoptosis, may prevent cancer
progression and metastasis by blocking signals necessary for
survival of localised cancer cells. Resistance to anoikis is
regarded as a prerequisite for metastasis.
* The anoikis-resistant cells have a reduced growth rate and are
more invasive than their respective adherent cell lines. The eect
of berberine on growth was compared to that of doxorubicine in
both the adherent and anoikis-resistant cell lines. Berberine
promoted the growth inhibition of anoikis-resistant cells to a
greater extent than doxorubicine treatment (Kim et al., 2010).
111 16/12/14
Panaxea Berberine Complex
* Berberine is an anticancer agent by three dierent cell lines
which were MCF-7, HepG-2, and Caco-2 cells by using neutral
red uptake assay which compared with control normal cells
(PBMC). Berberine chloride and barberry extract showed to
have inhibitory eect on the growth of breast, liver and colon
cancer cell lines (Abeer et al., 2013). Berberine has been
established to inhibit the growth of breast cancer cells.
* Treatment with berberine-induced cell cycle arrest at G0/G1 in
the anoikis-resistant MCF-7 and MDA-MB-231 cells as compared
to untreated control cells. These results revealed that
berberine can eciently inhibit growth by inducing cell cycle
arrest in anoikis-resistant MCF-7 and MDA-MB-231 cells (Kim et
al., 2010).
112 16/12/14
Panaxea CoryBer
* Gao et al., (2008) found that the yanhusuo extract inhibited the
migration and invasion of MDA-MB-231 cells in vitro. The
yanhusuo extract inhibited the mRNA expression and activity
of metalloproteinase-9 (MMP-9). The anti-cancer metastasis
eect of yanhusuo involved the activation of p38 and inhibition
of ERK1/2 and SAPK/JNK mitogen-activated protein kinase
(MAPK) signalling.
* Oh et al., (2010) identied the biological activity of yanhusuo
against cancer metastasis. Corydalis alkaloid (CA) inhibited LPS-
induced IL-8 production in a dose-dependent manner. CA
inhibited extracellular signal-regulated kinase and p38 MAPK
phosphorylation, which suggests that CA inhibits IL-8 secretion
by blocking MAPK phosphorylation. 113 16/12/14
Panaxea CoryBer
* Corydalis alkaloids Pain
containing * Research suggests that dl-
Tetrahydropalmatine (dl- THP blocks certain receptor
thp) sites (e.g., dopamine) in the
Rhizoma Coptidis Recens brain to cause sedation.
containing berberine (75%) Reports from Chinese
researchers have noted that
the herb was eective in
reducing pain in seventy-eight
per cent of the patients
tested (Oh et al., 2010).

drdweber@panaxea.com 114 16/12/14


Breast METS
* Hu et al., (2014) administered Chinese traditional herb drugs
called Fei Decoction to help a patient with breast cancer
multiple pulmonary and skeletal metastatic lesions. After
taking the Chinese herbs for 2 months, the tumour marker
(CEA, CA15-3) dramatically decreased, resulting in the normal
range.
* Both lung and bone metastatic sites reduced according to CT
and ECT imaging, and the patient felt free from the complaint
of pulmonary and cardiac discomfort.
* The PFS (progression-free-survival) and TTP (time-to-
progression) from the onset to date is notable.

drdweber@panaxea.com 115 16/12/14


Fei Decoction
* Semen Coicis (yi yi ren) * Semen Persicae (tao ren)
* Semen Persicae (tao ren) Radix Platycodonis
Semen Benincasae (dong grandiorum (jie geng)
gua zi) * Herba Houttuynia cordata (yu
* Radix Astragali xing cao)
membranaceus (huang qi)
* Radix Glehniae (bei sha shen)
* Bulbus Lilii (bai he)
Radix Cynanchi atrati (bai wei)
* Cortex albiziae (he huan pi) Radix Glycyrrhizae (gan cao)
Radix Ophiopogonis (mai
men dong) * Fructus Oryzae Germinatus
* Rhizoma bletillae (bai ji) Praeparata (jiao dao ya)
* Bulbus fritillariae cirrhosae * Fructus Hordei Germinatus
(chuan bei mu) 116
Praeparata (jiao mai ya) 16/12/14
Hyperprolactinaemia
* Prolactin levels were measured in 149 patients with advanced
metastatic breast cancer and Hyperprolactinaemia occurs in
44% of patients with metastatic breast cancer in the course of
the disease. HYPRL is associated with progressive breast
cancer in 88% of cases.
* It is concluded that HYPRL is of prognostic signicance and a
reliable indicator of progressive disease in advanced
metastatic breast cancer (Holtkamp et al., 1984).
* Hyperprolactinaemia is associated with aggressiveness of the
tumour, early disease relapse or metastases, and poor overall
survival in patients with node negative breast cancer (Patel et
al., 1996).
117 16/12/14
Hyperprolactinaemia
* The formula Huiru Yizeng Yihao signicantly decreased
prolactin (PRL) and increased oestradiol (E2), progesterone
(P), follicle stimulating hormone (FSH), luteinizing hormone
(LH) concentrations of hyperprolactinaemia rats.
* It decreased E2, PRL, FSH, gonadotropin-releasing hormone
(GnRH), 5-hydroxytryptamine (5-HT) and increased P
concentrations of human menopausal gonadotropin (hMG).
* Treatment could signicantly regulate the sex hormone
disorder of hyperprolactinemia (Wang et al., 2013).

118 16/12/14
Huiru Yizeng Yihao
* Mai Ya (Fructus Hordei Germinatus)
* Xia Ku Cao (Prunella vulgaris L.)
* Bai Shao (Paeonia lactiora) Pallas)
* Zhe Bei Mu (Fritillaria thunbergii Miq.
* Ru Xiang (Boswellia carterii Birdw.)
* Yu Jin (Curcuma aromatica Salisb.)
* Dan Shen (Salvia miltiorrhiza Bge.)
* Bai Jie Zi (Semen Brassicae)
* Mu Li (Ostrea gigas thunberg)
* Kun Bu (Laminaria japonica Aresch.)
drdweber@panaxea.com 119 16/12/14
Magnolol
* In this study, Liu et al., (2013) examined the eects of
magnolol (Mag), a compound extracted from medicinal
herbs, on breast cancer cells in vitro and in vivo.
* Highly invasive cancer cells were found to be highly sensitive
to treatment. Mag markedly inhibited the activity of highly
invasive MDA-MB-231 cells. Furthermore, Mag signicantly
downregulated matrix metalloproteinase-9 (MMP-9)
expression, an enzyme critical to tumour invasion.
* Mag suppresses tumour invasion by inhibiting MMP-9
through the NF-B pathway.

drdweber@panaxea.com 120 16/12/14


Scutellaria Barbata
* Scutellaria barbata (ban zhi lian) was used in women with
metastatic breast cancer (MBC). The trial was an open-label,
phase 1B, multicenter, dose escalation study. Eligible patients
had histologically conrmed breast cancer and measurable
stage IV disease.
* Investigator assessment classied three patients with stable
disease for >120 days (21%). One patient was on Scutellaria
barbata for 449 days and remains stable for 700 + days.
Independent radiology review identied three patients with
objective tumour regression (Perez et al., 2010).

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Objective Tests for TCM Pattern

Pattern Syndrome
zhng

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Genetic Polymorphisms
* The genetic mechanisms underlying syndrome dierentiation in
patients. Twenty-nine single nucleotide polymorphisms (SNPs) in
EGF, TGFA, and EGFR were investigated.
* Two SNPs, rs11466285 in TGFA and rs884225 in EGFR, were
signicantly associated with the distribution of ZHENG.
* The rs11466285 TT genotype increased the risk of damp heat with
toxin (DHT) and deciency of both Qi and yin (DQY) compared
with obstruction of blood stasis (OBS).

123
Genetic Polymorphisms
* The rs884225 AA genotype could increase the risk of DQY and
deciency of both Qi and blood (DQB) compared with yin
deciency due to stomach heat (YDSH).
* Parallel comparison among the SNPs and syndrome types
revealed that DQB was distinct from YDSH, disharmony between
the liver and stomach, stagnation of phlegm muddiness (SPM),
OBS, and other syndromes at several SNP loci (Zhang et al., 2013)

124
Toxic Heat and Chronic Inammation

Inammation

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Medicinal herbs for heat clearance
and detoxication ()
* Artemisia annua (qing hao) * Paeonia suruticosa (mu dan pi)
* Astragalus membranaceus * Paris polyphylla (zao xiu)
(huang qi) * Patrinia scabiosaefolia (bai jiang
* Coptidis Rhizoma (huang lian) cao)
* Erigeron breviscapus (deng zhan * Rabdosia rubescens (dong ling
xi xin) cao)
* (Houttuynia cordata (yu xing * Scutellaria baicalensis (huang qin)
cao) * Scutellaria barbata (ban zhi lian)
* Oldenlandia diusa (bai hua she * Solanum nigrum (long kui)
she cao)
* Sophora avescens (ku shen gen)
* Oroxylum indicum (gu zhi hua) * Vitex rotundifolia (man jing zi)

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Chronic Inammation
* About 95% cancer can link modern life style and environment
with inammation as the basic underlying cause (Anand et al.,
2008). Chronic or persistent tissue inammation or irritation
is correlated with adverse eects and has long been linked
with increasing rate of tumour formation by epidemiological
studies (Balkwill & Mantovani, 2001; Rossi & Sawatzky, 2008).
* Rudolf Virchow (1821-1902) observed frequent cancer
origination at the site of chronic irritation. His hypothesis was
that some classes of irritants, together with the tissue injury
and the ensuing inammation caused enhanced cell
proliferation (Parsonnet, 1999).

drdweber@panaxea.com 127 16/12/14


Chronic Inammation
* In China in the 7th Century, CE Chao Yuanfang (550-630)
reported, while working as an imperial physician, Qi and
water stagnation stays in the body, clustering as nodules
('lumps). Toxic Heat ghts Zheng Qi in the body, stagnating
and steaming the body, causing hypochondriac pain and
fullness.(Cultural China website)
* The Zhu Bing Yuan Hou Lun (Treatise on Causes and
Symptoms of Diseases, Vol. 12) was one of the rst to
mention Toxic Heat in regard to tumours (swellings) (Wong &
Wu, 1932).

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Chronic Inammation
* Infection and chronic inammation contribute to about 1 in 4
of all cancer cases (Blanco et al, 2007). Mediators of the
inammatory response, (e.g. cytokines, free radicals,
prostaglandins and growth factors) can induce genetic and
epigenetic changes including point mutations in tumour
suppressor genes, DNA methylation and post-translational
modications and this causes alterations in critical pathways
responsible for maintaining the normal cellular homeostasis
and leading to the development and progression of cancer
(Perwez-Hussain & Harris, 2007).

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Chronic Inammation
* In more recent times, Kevin Chan (1995) reports that the
source of Toxic Heat is TNF-, IL-6 and other inammatory
cytokines, combined with blood stasis, hypoxia and a
weakened cellular (Th1) immunity. The concept of Toxic Heat
in TCM is central to cancer treatments.
* From a more orthodox position, Dalgleish and OByrne (2006,
p. 5) state, it is recognised that cancer is a series of
stochastic events involving permanent activation of
oncogene pathways and deletion of tumour suppressor
genes, and in the face of chronic inammation, immune
induction does not occur and the mutated cell survives to
divide.
drdweber@panaxea.com 130 16/12/14
Chronic Inammation
* The tumour microenvironment consists of tumour, immune,
stromal, and inammatory cells which produce cytokines,
growth factors, and adhesion molecules that promote
tumour progression and metastasis.
* All intimately interact with one another and play an important
role in inammatory and pro-angiogenic processes and
promote tumor cell proliferation. Interestingly, there is an
association between chronic inammation and tumour
development or progression; 15% of all cancers are attributed
to inammatory aetiologies (Kuper, Adami , Trichopoulos,
2000).

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Chronic Inammation
* Serum IL-6 concentration was signicantly higher in patients
with breast cancer compared to healthy controls. Serum IL-6
level is the most discriminative factor separating healthy
controls and the loco-regional and metastatic breast cancer
patient groups.
* These results suggest a role for tumour-derived IL-6 in
regulating VEGF expression in platelets and their precursors
and also conrm the role of circulating platelets in the
storage of VEGF (Benoy et al., 2002).

drdweber@panaxea.com 132 16/12/14


Oncogenes and Tumour Suppressor
Genes
* There are two classes of genes that can control cancer
development. Oncogenes and tumour suppressor genes
belong to one class, while the other class belongs to the
caretaker genes.
* Healthy cells follow standard rules of growth and
proliferation, and have a denitive life span. In contrast, cells
with an oncogenic activation undergo much faster cell
division with an indenite life span. Tumour suppressor genes
are evolved to inhibit deregulated cell growth.

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NF-B and p53 Antagonise Each
Others Activity.

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The yin/yang of NF-kB/p53
* Various mediators involved in the pathways are indicated. In
addition, p53 and NF- B can inhibit each other by direct
physical interaction through their multimerisation domain.
Eventually, the eect of activation NF- B pathway prevents
the activation of p53 pathway and vice versa.
KEY: The black coloured upward arrows adjacent to NF- B and
p53 indicate activation of these transcription factors.
MDM2: mouse double mute 2; -TrCP1: beta transducing
repeat containing protein1; ARF: alternate reading frame
of INK4/ARF locus; ATR: ATM-Rad3 related; CHK: check
point kinase; I B: inhibitor of kB; IKK: inhibitor of
kappaB kinase.
drdweber@panaxea.com 135 16/12/14
NF-kB
* Coix lachryma-jobi (yi ren) seeds is currently the most
commonly used treatment for cancer in China and clinical
data support the use of this preparation of a TCM cancer
treatment. Coix seed extract also signicantly aects gene
expression in cells, including downregulation of genes (such
as COX-2 and matrixmetalloproteinases) that are considered
to be important in neoplasia.
* Coix extract inhibits activity of protein kinase C, a major
mediator of signal transduction and activator of NF-kB (Woo
et al., 2005).

drdweber@panaxea.com 136 16/12/14


Cancer Stem Cells
* The receptor CXCR1 is found on the cancer stem cells and
triggers growth of stem cells in response to inammation and
tissue damage. Investigation has suggested an important link
between inammation, tissue damage and breast cancer,
which may be mediated by cancer stem cells.
* Furthermore, anti-inammatory drugs may provide a means
of blocking these interactions, thereby targeting breast
cancer stem cells (Wicha 2010). Clearly, inammation due to
immune dysregulation plays a critical role in tumour initiation,
progression and metastases.

drdweber@panaxea.com 137 16/12/14


Cancer Stem Cells & EMT
* Morel et al., (2008) show that cells possessing both stem and
tumourigenic characteristics of cancer stem cells can be
derived from human mammary epithelial cells following the
activation of the Ras-MAPK pathway. The acquisition of these
stem and tumorigenic characters is driven by epithelial-
mesenchymal transition (EMT) induction.
* Overexpression of MMP-9 resulted in induction of the EMT in
these cells and this could be reversed by treating with
luteolin or quercetin. Co-treatment with epidermal growth
factor (EGF) plus luteolin or quercetin resulted in a more
epithelial-like morphology, led to reduced levels of EGF-
induced markers of EMT, and caused the restoration of cell
cell junctions (Lin et al., 2011).
drdweber@panaxea.com 138 16/12/14
TNF
* Tumour necrosis factor-alpha (TNF) has been implicated in
both cancer development and progression in some preclinical
models. In particular, as a central mediator of inammation,
TNF might represent one of the molecular links between
chronic inammation and the subsequent development of
malignant disease.
* Furthermore, deregulated TNF expression within the
tumour microenvironment appears to favour malignant cell
tissue invasion, migration and ultimately metastasis
formation (Mocellin & Nitti, 2008).

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Inammatory Cytokines
* Tumour initiation, growth and progression and many of these
eects are mediated by proinammatory cytokines. Among
these cytokines, the pro-tumourogenic function of TNF,
interleukin 6 & 1 (IL-6, IL-1) is well established (Akira et al.,
1990).
* Expression patterns of TNF, IL-1beta, IL-6 and IL-10, along
with transforming growth factor beta (TGF-) , were similar in
both parental and transformed cells. Considering all these
results, we conclude that various cytokines have discrete
roles in tumour promotion and cell transformation
(Suganuma et al., 2002).

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Inammatory Cytokines
* Chronic pathological inammation
is mediated via the continuing
presence of a persistent stimulus,
such as tumour cells, and the
resulting prolonged inammatory
cytokine exposure has the potential
to promote tumour growth
through the induction of angiogenesis, DNA damage, and
other events favourable to tumour invasion and metastases
(Balkwill & Mantovani, 2001). Tumours produce their own
inammatory factors.

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VEGF
* Vascular endothelial growth factor (VEGF) is a signal protein
produced by cells that stimulates vasculogenesis and
angiogenesis. It is part of the system that restores the oxygen
supply to tissues when blood circulation is inadequate.
* Elevated VEGF blood concentrations have been proven to be
associated with poor prognosis in human neoplasms. This
nding is generally explained as a consequence of the
potential angiogenic properties of VEGF itself. However,
preliminary experimental studies suggest that VEGF, in
addition to its angiogenic activity, may also play an
immunosuppressant role by inhibiting dendritic cell (DC)
maturation (Lissoni et al., 2001).
142 16/12/14
Herbs for Inammation
* Sumu (Lignum Sappan, ) was rst mentioned in Xin Xiu
Ben Cao (Newly Revised Materia Medica) by Su Jing in
657-659 CE and its action are said to activate Blood, open
channels and relieve pain.
* The aqueous extract of Lignum sappan (AELS) may markedly
decrease the level of TNF and IL-6 (Wang et al 2007), it has
also been shown it can kill cancer cell lines of HL-60, K562,
L929 and Yac-1 at the concentration of 2l/ml in vitro. The
survival time of mice treated with AELS is increased by 185%
(P0.01) by ip 0.2ml/mouse7d (Ren & Zhang 1990).

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Herbs for Inammation
* Radix Pulsatillae (bai tou weng) use goes back to the Shen
Nong Ben Cao Jing (2nd CE) and is said to clear Heat and
eliminate Toxin. It strongly inhibits the secretion of TNF, IL-1
and IL-6 from Kuper cells [KC] stimulated by
Lipopolysaccharide [LPS] (Hu et al, 2010).
* Xian and Qian (2009) state that bai tou weng is an innovative
antitumour-drug of high eect and low toxin. Triterpenoid
Saponins isolated from Pullsatilla Root appear to be an
important promoiety for the enhancement of anticancer
activity of their aglycones (Bang et al 2007).

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Herbs for Inammation
* Herba Portulacae oleracea (ma chi xian) may act on adipose
cells damaged by the high lipid serum to increase cell viability
and lower the levels of TNF- and IL-6 secreted by adipose
cell secreted (Xiao et al, 2005). Its use is rst mentioned in Xin
Xiu Ben Cao and is said to clear Heat and eliminate toxin
and also cools Blood and stops bleeding.
* Supernatant TNF- and IL-6 decrease signicantly after
Phytolacca acinosa (shang lu decoction) culture (Zhang et al,
2004) while Chrysanthemum indicum (ye ju hua) has an
inhibitory eect on sIL-2R, IL-6 and TNF- (Zhang et al, 2000).

drdweber@panaxea.com 145 16/12/14


Herbs for Inammation
* The serum levels of TNF-, IL-6 and IL-10 decrease following
baicalin treatment (Liu et al 2006). The avonoid baicalin,
isolated from the dried root of Scutellaria baicalensis (huang
qin) is widely used in the traditional Chinese herbal medicine
for its anti-inammatory, anti-pyretic and anti-hypersensitivity
eects.
* Apoptosis was enhanced by the combination treatment of
baicalin and baicalein, which activated caspases-3 and
caspase-9, downregulated the level of bcl-2 and upregulated
the level of bax or p53 via the ERK/p38 MAPK pathway (Zhou
et al., 2009).

drdweber@panaxea.com 146 16/12/14


Herbs for Inammation
* Baicalin with scutellarin (both from Scutellaria baicalensis),
and two extracts puried from Salvia miltiorrhiza (dan shen)
(SM-470, circulatory stimulant) and Camellia sinensis
(Cam-300, antipyretic), and examined their anti-proliferation
eects on the human breast cancer cell lines MCF-7 and
T-47D.
* All four compounds inhibited MCF-7 and T-47D cell
proliferation, SM-470, Cam-300, scutellarin and baicalin
inhibited the proliferation of human breast cancer cells as
well as CAL-27 and FaDu cells (Franek et al., 2005).

drdweber@panaxea.com 147 16/12/14


Herbs for Inammation
* Daidzein treatment resulted in decreases in cyclin D, CDK2,
and CDK4, whereas the expression of CDK6 and cyclin E was
unchanged. Daidzein treatment increased the expression of
the CDK inhibitors p21Cip1 and p57Kip2. Thus, daidzein exerts
its anticancer eects in human breast cancer cells via cell
cycle arrest at the G1 and G2/M phases (Peterson & Barnes,
1991).
* The isoavones daidzein and genistein inhibited iNOS protein
and mRNA expression and also NO production in a dose-
dependent manner. The results explain the pharmacological
ecacy of avonoids as anti-inammatory compounds
(Hmlinen et al., 2007).
drdweber@panaxea.com 148 16/12/14
Celprotect
* Radix Pueraria lobata (Ge Gen) (standardised Daidzein)
* Semen Sojae Praeparatum (Dan Dou Chi) (standardised
Glycitein) [Note: this methoxyisoavone is GMO free]
* Genista tinctoria (ran liao mu) (extract Genistein 99%)
* Radix Scutellariae Baicalensis (Huang Qin) (standardised
Baicalein)
* Radix Scutellariae Baicalensis (Huang Qin) (standardised
Baicalin)
* Fructus Gardeniae Jasminoidis (Zhi Zi) (standardised
Jasminoidin)

drdweber@panaxea.com 149 16/12/14


ICC
(Inammation Control Compound)
* Radix Stephania tetrandra (fen fang * Reduces various
ji) contains extract 15% Tetrandrine, inammatory mediators,
5% Fangchinoline including interleukin-6 (IL-6),
* Folium Urticae dioica extract IL-1 beta, TNF-,
* Folium Ocimum sanctum contains prostaglandin E2 and
extract 2.5% Ursolic acid leukotrienes.
* Radix Zingiber ocinale (sheng * Rare side-eects may include
jiang) contains extract 20% gingerols diarrhoea, skin rash, acid
reux and nausea and may
* Gum Boswellia serrata contains be contraindicated in those
extract 30% AKBA with pre-existing gastritis or
* EGCG gastro-oesophagael reux
* Terminalia chebulla (he zi) contains disease (GORD).
extract Luteolin 90% 150 16/12/14
Luteolin
* Luteolin, a plant-derived avonoid, is thought to inhibit tumour
growth due to its strong inhibitory eect on nuclear factor
(NF)-B.
* Results suggest that AMPK activity is critical for the inhibition
of cancer cell growth, possibly via modulation of NF-B
activity. Hwang et al., (2011) showed that luteolin treatment
causes the release of reactive oxygen species (ROS) and that
these intracellular ROS in turn mediate AMPK-NF-B signalling
in cancer cells.
* Having multiple biological eects such as anti-inammation,
anti-allergy and anticancer, luteolin functions as either an
antioxidant or a pro-oxidant biochemically (Yin et al., 2008).
drdweber@panaxea.com 151 16/12/14
Cryptotanshinone
* Cryptotanshinone (CTSO) is a major constituent of
tanshinones, which are extracted from the medicinal herb
Salvia miltiorrhiza (dan shen) and have well-documented anti-
oxidative and anti-inammatory eects.
* CTSO can reduce prostaglandin E2 synthesis and reactive
oxygen species generation catalysed by COX-2, without
inuencing COX-1, and is directed against enzymatic activity
of COX-2 (Jin et al. 2006).

drdweber@panaxea.com 152 16/12/14


Tanshinone IIA
* Tanshinone IIA (Tan IIA) could serve as a potential selective
oestrogen receptor modulator (SERM) to treat inammation
without increasing the risk of breast cancer. It exerts anti-
inammatory eects by inhibition of iNOS gene expression
and NO production, as well as inhibition of inammatory
cytokines IL-1, IL-6, and TNF- (Fan et al., 2009).
* Tan IIA could also decrease the expression of TNF- and
activation of nuclear transcription factor-kappa B (NF-B)
(Ren et al., 2010)

drdweber@panaxea.com 153 16/12/14


Panaxea Tanshins
* Salvia Miltiorrhiza (contains extract Tanshinone IIA and
Cryptotanshinone)
Note:
* TANSHINS signicantly increase the activity of CYP1A2 in a
dose-dependent manner. CTS can induce hepatic microsome
CYP1A2 expression signicantly, which indicates potential
drug-drug interaction might occur when CTS is co-
administrated with those drugs metabolised by CYP1A2 such as
Capecitabine / Capecitabine (Xeloda), Lapatinib / Lapatinib
(Tykerb)
* Long term use may increase DHEA-S
drdweber@panaxea.com 154 16/12/14
Blood Stasis

Coagulation Factors

drdweber@panaxea.com 155 16/12/14


Blood Stasis
* Drugs with the ecacy of modifying rheological properties of
blood, blood vessels and their interactions are denoted by
haemorheologicals. Drugs of anti-hyperviscosaemia, anti-
coagulants, anti-platelet drugs, anti-thrombotics, vasodilators,
endothelial cell protectors and anti-arthrosclerosis should be
considered as haemorheologicals due to the actions in keeping
blood iudity and in maintaining normal vascular functions.
* Haemorheologicals are importance for and ageing and life-
threatening diseases. Blood Stasis syndrome is a common
pathological syndrome in the elderly. In traditional Chinese
medicine, the treatment for the syndrome is by herbs which
activates blood circulation to remove Blood Stasis (Liao ,
2000). 156 16/12/14
Blood Stasis
* Clot formation on the tumour cells facilitates tumour cell
spreading, improving the attachment to the endothelium and
enhancing tumour cell survival and metastasis (Im et al., 2004).
Platelets surrounding tumour cells release growth factors and
chemokines (VEGF, ILGF1, TGF-) that enhance tumour cell
proliferation and angiogenesis (Gay & Felding-Habermann.,
2011).
* Direct interaction between platelets and tumour cells triggers
Epithelial to mesenchymal transition (EMT) through platelet
derived TGF-/SMAD and NF-B pathways (Labelle et al., 2011).
Multiple mechanisms have the potential to contribute to
metastasis enhancement by coagulation and platelet
aggregation by tumour cells. 157 16/12/14
Blood Stasis & NK Cells
* The idea of using immune tonics may be a fruitless pursuit.
* The aggregation of platelets around tumour cells in tissue
culture greatly diminishes the ability of Natural Killer (NK)
cells to lyse cancer cells in culture (Bobek et al, 2005).
* Consistent with these ndings, activation of platelets and the
presence of brinogen have been shown to help tumour cells
to evade immune surveillance mechanisms, protecting them
from killing by NK cells (Palumbo et al, 2005, 2007), by both
physical means and through signalling that leads to NK
quiescence (Stewart, Vivier & Colonna, 2006; Kopp, Placke &
Salih, 2009).

drdweber@panaxea.com 158 16/12/14


Blood Stasis
* Chinese herbal medicine contributes a great deal to the health of the
Chinese nation. Blood stasis syndrome (BSS) is a signicant
pathological syndrome in TCM.
* The approach of treatment for BSS is activating blood circulation to
remove blood stasis (ABCRBS). Herbs of ABCRBS are a category of
over 10% in the modern Chinese Pharmacopoeia (Volume I Herbal
Medicine volume).
Medicinal for promoting blood circulation and eliminating stasis in
cancer ()
* Curcumae longae (jiang huang) Achyranthes Longifolia (tu niu xi)
* Curcumae wenyujin (yu jin) Squama Manis (chuan shan jia)
* Leonurus japonicus (yi mu cao) Caulis Spatholobu (ji xue teng)
* Panax notoginseng (san qi) Rhizoma Sparganii (san leng)
* Rheum ocinale (da huang) Rhizoma Curcumae (e zhu)
* Salvia miltiorrhiza (dan shen) Eupolyphaga (di bie chong)
159 16/12/14
Pro Creation R Capsules
* Radix Angelica sinensis (dang gui)
* Radix Ligusticum wallichii (chuan xiong)
* Radix Salvia miltiorrhiza (dan shen)
* Semen Prunus persicae (tao ren)
* Fructus Liquidamber taiwaniani (lu lu tong)
* Fructus Gleditsia sinensis (zao jiao)
* Radix Saussurea lappa (mu xiang)
* Radix Paeonia lactiora (chi shao)
* Rhizoma Corydalis (yan hu suo)
* Frucus Melia toosendan (chuan Lian zi)
* Radix Bupleurum chinense (chai hu)
drdweber@panaxea.com 160 16/12/14
Blood Stasis Formulations
* Xiongshao capsule: Rhizoma Ligustici Chuanxiong, Radix
Paeoniae Rubrae (chi shao)
* Taohongsiwu decoction: Semen Persicae (tao ren), Flos
Carthami (hong hua), Rhizoma Ligustici Chuanxiong, Radix
Angelica sinensis (dang gui), Radix Paeoniae Alba (bai shao),
Radix Rehmanniae Praeparata (shu di)
* Xue Fu Zhu Yu Tang: Semen Pruni Persicae (tao ren), Radix
Ligustici Chuanxiong, Flos Carthami Tinctorii (hong hua), Radix
Angelicae Sinensis (dang gui), Radix Paeoniae Rubrae (chi
shao), Radix Cyathulae Ocinalis (chuan niu xi), Radix
Rehmanniae Glutinosae (sheng di), Radix Bupleuri (chai hu),
Radix Platycodi Grandiori (jie geng), Fructus Citri Aurantii (zhi
ke), Radix Glycyrrhizae Uralensis 161
(gan cao) 16/12/14
Panaxea Blood Stasis Granule
* Buyanghuanwu (BYHW) Granules: Radix Astragalus (huang
qi), Semen Persicae (tao ren), Flos Carthami (hong hua),
Rhizoma Ligustici Chuanxiong, Radix Angelica sinensis (dang
gui), Radix Paeoniae Rubrae (chi shao), Pheretima /
earthworm (di long)
(All above: Liu et al., 2012)
* BYHW is an historical and empirical formula that is now being
researched extensively in China. This research includes
cardiovascular system diseases including DVT, spinal injuries,
motor and nervous system diseases including migraine,
metabolic diseases, respiratory and digestive diseases, and
cancer (see Panaxea research database).
drdweber@panaxea.com 162 16/12/14
ji xue teng
* The Chinese herb Spatholobus suberectus (ji xue teng) is
commonly prescribed to cancer patients. In this study, the
anti-cancer eect of SS and its molecular mechanisms have
been investigated. Cell growth assay showed that SS
eectively inhibits tumour cell growth in a dose-dependent
manner and experiments show that the eciency of SS alone
group was superior to docetaxel or to docetaxel and SS
combined.
* SS is a potential herb for cancer treatment by inhibiting
tumour growth via induction of apoptosis and arrest of the
cell cycle at G2/M phase (Wang et al., 2011).

drdweber@panaxea.com 163 16/12/14


Oridonin
* Rabdosia rubescens (dong ling cao) is a Chinese medicinal herb
used widely. The aerial parts of RR and other species of the
same genus has been reported to have the functions of
clearing heat and toxicity, nourishing yin, removing
blood stasis, and relieving swelling (Tang & Eisenbrand,
1992).
* RR and its extracts have been shown to be able to suppress
disease progress, reduce tumour burden, alleviate syndrome
and prolong survival in patients (Henan Medical Institute, 1978)
* Oridonin, was isolated from RR and was shown to be a potent
apoptosis inducer in a variety of cancer cells (Fujita et al., 1988;
Zhou et al., 2007)
164 16/12/14
Panaxea OriJi
* Oridonin extract 40%
* Supercritical extract of Spatholobus suberectus 60%

drdweber@panaxea.com 165 16/12/14


Fibrosis
* Fibrotic disorders of the liver, kidney and lung are associated
with excessive deposition of extracellular matrix proteins and
on-going coagulation-cascade activity. In addition to their
critical roles in blood coagulation, thrombin and the
immediate upstream coagulation proteases, Factors Xa and
VIIa, inuence numerous cellular responses that may play
critical roles in subsequent inammatory and tissue repair
processes in vascular and extravascular compartments.
* Coagulation proteases have also been shown to play a role in
the pathogenesis of brosis (Chambers & Laurent, 2002).

drdweber@panaxea.com 166 16/12/14


Fibrosis
* Serine protease inhibitors (serpin) play a central role in
various pathological processes including coagulation,
brinolysis, malignancy, and inammation. Plasminogen
activator inhibitor-1 (PAI-1) is a key serpin (Yuko et al., 2008).
* Proteolytic degradation of extracellular matrix (ECM)
components during tissue remodeling plays a pivotal role in
normal and pathological processes including wound healing,
inammation, tumour invasion, and metastasis (Park et al.,
1999).
* Protease inhibitors are emerging as potentially therapeutic
tools to treat cancer (DeClerck & Imren, 1994).

drdweber@panaxea.com 167 16/12/14


Fy)Brox
* Quercetin (Flos Sophorae * Anti-brotic in total collagen
extract) accumulation
* Baicalein Scutellaria baicalensis
extract) * Anti-nodule formation
* Baicalin (Scutellaria baicalensis * Blood Buster
extract) * Fibrosis, characterised by
* Salvianolic Acid B (Salvia extracellular matrix (ECM)
Miltiorrhiza extract)
accumulation and disruption of
* Emodin (Rheum Palmatum
extract)
normal tissue architecture, is
the common cause of chronic
* Scutellaria Baicalensis (huang
qin) failure of many organs
* Salvia Miltiorrhiza (dan shen)
* Rheum Palmatum (da huang) 168 16/12/14
Congested Interstitial Fluid & the Extracellular Matrix

Phlegm Damp

drdweber@panaxea.com 169 16/12/14


Phlegm Damp
* The phlegm-dampness constitution is one of the nine
constitutions and is the most common type in constitution
study. Genomics studies found four upregulated genes:
COPS8, GNPDA1, CD52 and ARPC3; and six downregulated
genes: GSPT2, CACNB2, FLJ20584, UXS1, IL21R and TNPO in the
phlegm-dampness constitution.
* Gene functional analyses on genes aecting the dierences
between the phlegm-dampness constitution and the balanced
constitution indicated that people with phlegm-dampness
have a much higher risk of obesity, metabolic syndrome,
hypertension, hyperlipaemia and diabetes (Wang et al., 2013).

drdweber@panaxea.com 170 16/12/14


Phlegm Damp
* E-cadherin (E-cad) is a subclass of the cadherin family that
plays a major role in maintenance of intercellular junctions in
epithelial tissues (Oka et al., 1993).
* There is a signicant dierence in E-cad expression between
the stagnation of phlegm-damp type and the deciency in
both qi and blood and the deciency-cold of stomach and
spleen types, where E-cad expression was high.
* E-cad expression is relatively low in the internal obstruction of
stagnant toxin type and the in-coordination between liver and
stomach type, where tumour development and metastasis
may be associated with low E-cad expression, or with low
homogeneous adhesiveness between tumour cells (Sun et al.,
2007).
171 16/12/14
Phlegm Damp
* It is suggested that cell dissociation in tumours is
accomplished by loss of function or expression of the
epithelial cell adhesion molecule E-cadherin, and through the
activity of cell motility factors, like scatter factor.
* A striking feature of metastatic cells is the considerable
exibility in their adhesive interactions with other cells or
components of the extracellular matrix (Behrens, 1993).
* Oka et al., (1993) found signicant correlations between E-cad
expression and clinicopathological features. The frequency of
reduced E-cadherin expression (Rd type) was signicantly
higher in invasive ductal carcinomas (58%) and poorly
dierentiated carcinomas (84%) than in noninvasive and well-
dierentiated carcinomas. 172 16/12/14
Phlegm Damp
* The local microenvironment, or niche, of a cancer cell plays
important roles in cancer development. A major component of
the niche is the extracellular matrix (ECM), a complex network
of macromolecules with distinctive physical, biochemical, and
biomechanical properties.
* ECM is commonly deregulated and becomes disorganised in
diseases such as cancer. Abnormal ECM aects cancer
progression by directly promoting cellular transformation and
metastasis (Lu, Weaver, Werb, 2012).
* A direct link between hypoxia and the composition and the
organisation of the ECM, which suggests a new model in
which multiple microenvironmental signals might converge to
synergistically inuence metastatic outcome (Gilkes, Semenza,
Wirtz, 2014). 173 16/12/14
Phlegm Damp
* Interactions between the cell and the ECM are critical in
controlling the fate and behaviour of cancer cells. Alterations
in either the ECM or in cellular events aect this interaction.
give an overview of the role of cellECM interactions in
cancer, with a particular focus on the reciprocal nature of the
cellECM interactions and how this contributes to cancer
progression (van Dijk, Gransson, Strmblad, 2013).
* Fibrillar collagens, bronectin, hyaluronan and matricellular
proteins are matrix components that are common to both
involution and cancer. Moreover, some of these proteins have
in recent years been identied as important constituents of
metastatic niches in breast cancer (Oskarsson, 2013).
174 16/12/14
Phlegm Damp
* Much of the mass of a solid tumour is comprised of the
stroma which is richly invested with extracellular matrix.
Within this matrix are a host of matricellular proteins that
regulate the expression and function of a myriad of proteins
that regulate tumourigenic processes.
* One of the processes that is vital to tumour growth and
progression is angiogenesis, or the formation of new blood
vessels from preexisting vasculature. Within the extracellular
matrix are structural proteins, a host of proteases, and
resident pro- and antiangiogenic factors that control tumour
angiogenesis in a tightly regulated fashion (Campbell et al.,
2010).
175 16/12/14
Cell Adhesion Molecules
* Cell adhesion molecules (CAMs) are proteins located on the cell
surface involved in binding with other cells or with the
extracellular matrix (ECM) in the process called cell adhesion.
* Integrins, one of the major classes of receptors within the ECM,
mediates cell-ECM interactions with collagen, brinogen,
bronectin, and vitronectin. Integrins provide essential links
between the extracellular environment and the intracellular
signalling pathways, which can play roles in cell behaviours such
as apoptosis, dierentiation, survival, and transcription.
* The extracellular domain has major repeats called extracellular
cadherin domains. Sequences involved in Ca2+ binding between
the ECDs are necessary for cell adhesion.
drdweber@panaxea.com 176 16/12/14

ECM
* In biology, the extracellular
matrix (ECM) is a collection
of extracellular molecules
secreted by cells that
provides structural and
biochemical support to the surrounding cells.
* Because multicellularity evolved independently in dierent
multicellular lineages, the composition of ECM varies between
multicellular structures; however, cell adhesion, cell-to-cell
communication and dierentiation are common functions of
the ECM (Abedin & King, 2010)

drdweber@panaxea.com 177 16/12/14


Interstitial Fluid
* Interstitial uid is a solution that bathes and surrounds the
cells of multicellular animals. It is the main component of the
extracellular uid, which also includes plasma and transcellular
uid. The interstitial uid is found in the interstitial spaces, also
known as the tissue spaces.
* Interstitial uid bathes the cells of the tissues. This provides a
means of delivering materials to the cells, intercellular
communication, as well as removal of metabolic waste.
* Extravascular or interstitial factors may contribute signicantly
to the inammatory process including production of IL-6(doi:
10.1113/jphysiol.2011.206136)

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Interstitium
* The interstitium or interstitial space describes the space
outside the blood and lymphatic vessels. It contains two
phases; the interstitial uid (IF) and the extracellular matrix.
It consists of a solid or matrix phase and a uid phase (Gel/
Sol) together constituting the tissue microenvironment.
* Accumulated data show that tumour interstitial uid (IF) is
hypoxic and acidic compared with subcutaneous IF and
plasma, and that there are gradients between IF and plasma
giving information on where substances are produced and
thereby reecting the local microenvironment.

drdweber@panaxea.com 179 16/12/14


Phlegm Damp
* Is Phlegm Damp or hidden phlegm a disregulation of uids and
the attendant components?
* Among the several dierent forms of cell interactions known to
exist in multicellular organisms intercellular communication
provides the most direct form of communication by allowing
free exchange of ions and small molecules between
neighbouring cells via permeable membrane junctions. This
type of communication has been implicated in various
biological functions such as cell dierentiation, embryonic
development, and tissue growth regulation (Azarnia & Larsen,
1977).
* There is a signicance in cell junction dysregulation in cancer.
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MMTV-Wnt-1

Mammary Tumour Virus

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MMTV-Wnt-1
* In human breast cancers, a phenotypically distinct minority
population of tumourigenic (TG) cancer cells (sometimes
referred to as cancer stem cells) drives tumour growth.
Studies suggest that there is a cancer stem cell compartment
in the MMTV-Wnt-1 breast tumours (Cho et al., 2008).
* The expression of the Wnt-1 proto-oncogene can induce
mammary hyperplasia and tumourigenesis in the absence of
ER in females and in males.

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Ursolic Acid
* All ursolic acid (UA) doses decreased tumour cell proliferation
and UA at 0.10% mg/kg body weight/day was most eective in
inhibiting tumour take and decreasing nal tumour size.
Modulation of Akt/mTOR signalling and induction of
apoptosis appeared to mediate these eects on tumour
growth.
* UA potently disrupted cell cycle progression and induced
necrosis in a clonal MMTV-Wnt-1 mammary tumour cell line in
vitro. This study supports the potential of UA as an anti-
tumourigenic agent (De Angel et al., 2010).

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Stage 0 Pre-cancerous lesions

DCIS & LCIS

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DCIS
* Ductal carcinoma in situ (DCIS) is encountered much more
frequently in the screening population compared to the
symptomatic setting. The behaviour of DCIS is highly variable
and this presents diculties in choosing appropriate
treatment strategies for individual cases. DCIS accounts for 5
to 20% of cancers.
* Untreated, up to 50% of DCIS lesions progress to invasive
disease, and that the time for progression may be up to four
decades (Saunders et al, 2005; Collins et al., 2005).
* Ten years after DCIS diagnosis, 98% to 99% of women will be
alive.

drdweber@panaxea.com 185 16/12/14


DCIS Interventions
* The natural history of DCIS remains to be elucidated, and it is
unclear whether all DCIS cases progress to invasive breast
cancer. Surgery plus radiation therapy or mastectomy is
recommended for women in whom this potentially non-
progressive cancer is detected.
* Regina Dehen (2013) supports the developing trend toward
active surveillance in lieu of breast-disguring surgery and
oers evidence that CAM therapies including herbs and
acupuncture may be of value in preventing progression of
DCIS to invasive breast cancer.

drdweber@panaxea.com 186 16/12/14


DCIS Interventions
* Yanghe Huayan Decoction (YHD) Cornu Cervi Degelatinatium
(lu jiao shuang) 12 g, prepared rhizome of rehmannia (shu
di) 9 g, Cortex Cinnamomi (rou gui) 6 g, Semen Sinapis (bai
jie zi) 3 g, Radix Curcumae (yu jin) 12 g, Psuedobulbus
Cremastrae (shan ci gu) 15 g, Bulbus Frittillariae Thunbergii
(zhe bei mu) 9 g, licorice root (gan cao) 6 g at the daily dose
of 7.2 g/kg.
* YHD could partially inhibit and reverse canceration of DCIS.
It also could inhibit ki67 protein and mRNA expression. Its
eect was similar to tamoxifen.
* It is suitable for prevention and treatment of precancerous
lesions of breast cancer (Li et al., 2014).
187 16/12/14
Panaxea Cruciferous
* DIM is a new class of ER-selective compounds, because it
does not bind to ER, but instead it selectively recruits ER
and co-activators (Vivar et al, 2010)
* DIM can induce apoptosis in breast cancer cells independent
of oestrogen receptor status by a process that is mediated by
the modulated expression of the Bax/Bcl-2 family of
apoptotic regulatory factors (Biochemical Pharmacology
2002).
* I3C acts through a pathway that is distinct from either DIM or
tamoxifen in regulating CDK2 enzymatic activity (The Journal
of Biological Chemistry 2005).

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Panaxea Cruciferous
* DIM-treated subjects, relative to placebo, showed a signicant
increase in levels of 2-OHE1, DIM, and cortisol, and a non-
signicant increase of 47% in the 2-OHE1/16alpha-OHE1 ratio
from 1.46 to 2.14. In this pilot study, DIM increased the 2-
hydroxylation of oestrogen urinary metabolites (Dalessandri
et al., 2004).
* Results of a study by Nicastro et al., (2013) demonstrate the
important role of hepatocyte growth factor (HGF) and c-Met
(also called hepatocyte growth factor receptor) in DIM's anti-
proliferative eect on breast cancer cells and suggest that
DIM could have preventive or clinical value as an inhibitor of c-
Met signalling.
drdweber@panaxea.com 189 16/12/14
Empirical and Researched Formulas

Breast Cancer Granules


for Stages

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Stages
* Breast cancer staging using the TNM system is based on the size of
the tumour (T), whether or not the tumour has spread to the
lymph nodes (N) in the armpits, and whether the tumour has
metastasised (M). Larger size, nodal spread, and metastasis have a
larger stage number and a worse prognosis.
The main stages are:
* Stage 0 is a pre-cancerous or marker condition, either ductal
carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS).
* Stages 13 are within the breast or regional lymph nodes.
* Stage 4 is 'metastatic' cancer that has a less favourable
prognosis (NCI: accessed Aug 2014).
* The dierence between the two classications of grade and stage
is that the former views the status from pathology and the latter
views it from the cancer cell migration.
drdweber@panaxea.com 191 16/12/14
Stages
Stage 5 Year Survival
DCIS 93%
I 88%
IIA 81%
IIB 74%
IIIA 67%
IIIB 41%
IIIC 49%
IV 15%

Younger women tend to have a poorer prognosis than post-menopausal


women due to several factors. Their breasts may change with their menstrual
cycles, they may be nursing infants, and they may be unaware of changes in
their breasts. There may also be biologic factors including greater inammatory
factors contributing to a higher risk of disease recurrence for younger women
with breast cancer (Peppercorn, 2009). 16/12/14
Empirical Formulas
Cancer courses
Before operation
1. Liver Qi depression and phlegm stasis syndrome: Tiao Shen
Gong Jian Tan
2. Turbid phlegm and blood stasis: Xue Yu Zhu Yu Tang and/or
Xiao Yao Lou Bei San
3. Chong-Ren imbalance syndrome: Er Xian Tang.
4. Deciency of the vital principle and poison blazing: Ba Zhen
Tang w/ sheng di, mu dan pi, qing dai, shui niu jiao (ban mao,
chan su)
TCM indications and Chinese herbs (Lin et al., 2006)

drdweber@panaxea.com 193 16/12/14


Empirical Formulas
Cancer courses
After operation
1. Syndrome of incoordination between spleen and stomach:
Si Jun Zi Tang (not with ER+ tumours)
2. Two deciency syndrome of Qi and blood (Yin): Ba Zhen
Tang w/ mai dong, nu zhen zu (not with ER+ tumours)
3. Qi deciency and blood stasis: Yi Qi Huo Xue Tang
Period of consolidation
1. Two deciency syndrome of Qi and blood (Yin): Yi Qi Yang
Rong Tang
2. Deciency of spleen and kidney: Jin Kui Shen Qi Wan
3. Chong-Ren imbalance syndrome: Er Xian Tang
drdweber@panaxea.com 194 16/12/14
Breast Cancer Stage 1
Pattern: Phlegm and qi Stagnation
* Radix Angelicae Sinensis (dang gui)
* Radix Paeoniae Lactiorae (bai shao)
* Radix Pseudostellariae (tai zi shen)
* Sclerotium Poriae Cocos (fu ling)
* Radix Bupleuri (chai hu)
* Pericarpium Citri Reticulatae (chen pi)
* Semen Trichosanthis (gua lou ren)
* Bulbus Fritiliariae Cirrhosae (chuan bei mu)
* Tuber Curcumae (yu jin)
* Spica Prunellae Vulgaris (xia cu cao)
* Rhizoma Iphigeniae Indicae (shan ci gu)
drdweber@panaxea.com 195 16/12/14
Breast Cancer Stage 2 & 3
Pattern: Heat and Blood Stasis
* Herba Taraxaci Mongolici cum Rd (pu gong ying)
* Herba Solani Nigri - Long Kui
* Radix Arnebiae seu Lithospermi - Zi Cao
* Spica Prunellae Vulgaris - Xia Ku Cao
* Radix Trichosanthis Kirilowii - Tian Hua Fen
* Semen Vaccariae Segetalis - Wang Bu Liu Xing
* Pericarpium Citri Reticulatae Viridae - Qing Pi
* Bulbus Fritillariae Thunbergii - Zhe Bei Mu
* Radix Bupleuri - Chai Hu
* Fructus Viticis - Man Jing Zi
drdweber@panaxea.com 196 16/12/14
Breast Cancer Stage 4
Pattern: Toxic Heat and qi & yin Deciency
* Flos Lonicerae Japonicae - Jin Yin Hua
* Herba Taraxaci Mongolici cum Rd - Pu Gong Ying
* Rhizoma Paridis - Zao Xiu
* Herba Scutellariae Barbatae - Ban Zhi Lian
* Radix Rehmanniae Glutinosae - Sheng Di
* Tuber Ophiopogonis Japonici - Mai Men Dong
* Herba Dendrobii - Shi Hu
* Radix Scrophulariae Ningpoensis - Xuan Shen
* Radix Hibiscus - Fu Rong
* Sclerotium Poriae Cocos - Fu Ling
* Radix Pseudostellariae - Tai Zi Shen
* Radix Astragali Membranacei - Huang Qi
* Herba Gynostemma pentaphyllum - Jiao Gu Lan 16/12/14
Tests
* Hyper coagulation: Fibrinogen, D-Dimer, Anti-thrombin III,
and Plasminogen Activator Inhibitor 1 (PAI-1) and uPA
* Tissue Factor (TF) and Blood Coagulation
* Inammation: C-reactive Protein, ESR (SED rate), IL-6 and
TNF, Serum amyloid A
* Markers of Angiogenesis: Vascular Endothelial Growth Factor
(VEGF), Interleukin (IL)- 8, cathepsin B, Survivin, Matrix
Metalloproteinases (MMP)-2 and 9, HIF-1a, Hepatocyte
Growth Factor (HGF), epidermal growth factor (EGF) and its
receptor EGFR, Fibroblast Growth Factor-2 (FGF-2)
* Melatonin
drdweber@panaxea.com 198 16/12/14
Chemo, Radiotherapy, Tamoxifen & SEEMs, Immune
Function, Aerobic Glycolysis, MDR

Additional Protocols

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Panaxea A1 Mark II
* Angiogenesis is an essential event during the excessive growth
and metastatic spread of solid tumours. Anti-angiogenic
agents have become a new choice of therapy for patients with
cancer.
* In this study, Jiang et al., (2012) investigated the potential
eect of Yangzheng Xiaoji (A1- Mark2), a traditional Chinese
medicinal formula presently used in the treatment of several
solid tumours on angiogenesis.
* It markedly inhibited in vitro tubule formation from vascular
endothelial cells. They demonstrated that the extract has a
concentration-dependent inhibitory eect on cell-matrix
adhesion and cellular migration (Ye et al., 2012).
drdweber@panaxea.com 200 16/12/14
A1 Mark II
* Radix Astragali (huang qi)
* Fructus Ligustri Lucidi (nu zhen zi)
* Radix Ginseng (ren shen)
* Rhizoma Curcumae Ezhu (e zhu)
* Fructicatio Ganodermatus (ling zhi)
* Herba Gynostemma pentaphyllum (jiao gu lan)
* Rhizoma Atractylodis Macrocephalae (bai zhu)
* Herba Scutellariae Barbatae (ban zhi lian)

201
A1 Mark II
(continued)
* Herba Hedyotiolis Diusae (bai hua she she cao)
* Sclerotium Poriae Cocos (fu ling)
* Eupolyphaga sinensis (di bie chong)
* Endothelium Corneum Gigeriae Galli (ji nei jin)
* Duchesnea indica (She Mei)
* Herba Solani Lyrati (shu yang quan)
* Herba Artemisiae Capillaris (yin chen Hao)
* Radix Cynanchi Paniculatii (xu chang qing)

202
Protocols
Pre-chemo, radiotherapy and Concurrent to radiotherapy
surgery * Protect yin & Fluids
* Strengthen qi and Blood * Clear Heat Toxin
* Clear qi Stagnation and Blood Post chemo and radiotherapy
Stasis * Tonify qi, Blood, yin / yang
* Clear Phlegm
* Gently move qi and Blood
* Clear Toxic Heat
Concurrent to chemotherapy
* Protect Essence & Warm
Channels
* Clear Toxins
* Protect qi
203 16/12/14
Panaxea Chem1 Caps
* Radix Panax ginseng (ren * Fructus Amomum villosum
shen) (sha ren)
* Radix Atractylodes * Radix Astragalus
macrocephala (bai zhu) membranaceus (huang qi)
* Rhizoma Dioscoreae (shan * Semen Ziziphus jujuba var.
yao) spinosa (suan zao ren)
* Root Inula helenium (tu mu * Radix Polygala tenuifolia
xiang) (yuan zhi)
* Pericarpium Citrus aurantium * Radix Coptis chinensis (huang
(zhi ke) lian)
* Radix Panacis Quinquefolii (xi
drdweber@panaxea.com 204 yang shen) 16/12/14
Panaxea Chem1 Caps
* Chem 1 caps has been found to have a number of eects on
both innate and adaptive immune processes, with potential
indirect anticancer activity in in vivo studies. No side eects
were observed treated with the botanical compound, and no
negative eects were observed on the response to
chemotherapy or tumour mass.
* No toxic eects were attributed by patients to the Chem 1
caps treatment, and 85% reported that they believed the
botanical compound had helped reduce symptoms of breast
cancer chemotherapy treatment (Rachmut et al., 2013).

drdweber@panaxea.com 205 16/12/14


Panaxea CTF
(Chemotherapy Granules)
* Radix Ginseng (ren shen)
* Radix Codonopsis Pilosulae (dang shen)
* Radix Astragali Membranacei (huang qi)
* Radix Angelicae Sinensis (dang gui)
* Folium Dichroae Febrifugae (shu di)
* Radix Polygoni Multiori (he shou wu)
* Gelatinum Corii Asini (e jiao)
* Fructus Lycii (gou qi zi)
* Caulis Millettiae Reticulatae (ji xue teng)
* Tuber Ophiopogonis Japonici (mai men dong)
* Rhizoma Polygonati (huang jing)
* Herba Leonuri Heterophylli (206 yi mu cao) 16/12/14
Panaxea
CTF (Chemotherapy Granules)
(continued)
* Fructus Ligustri Lucidi (nu zhen zi)
* Herba Dendrobii (shi hu)
* Mori Albae Fructus (sang shen)
* Herba Epimedii (yin yang huo)
* Semen Cuscutae Chinensis (tu si zi)
* Fructus Psoraleae Corylifoliae (bu gu zhi)
* Sclerotium Cordyceps Chinensis (dong chong xia cao)
* Herba Cynomorii Songarici (suo yang)
* Fructus Alpiniae Oxyphyllae (yi zhi ren)
* Radix Morindae Ocinalis (ba ji tian)
* Cortex Eucommiae Ulmoidis (du zhong)
* Radix Salviae Miltiorrhizae (dan
207 shen) 16/12/14
Warburg Eect
* Aerobic glycolysis is inecient from the standpoint of ATP
production, but it provides cancer cells with biomolecules
implicated in the synthesis of lipids and nucleotides required for
cellular proliferation. Thus, targeting aerobic glycolysis has clearly
been recognized as a potentially fruitful approach for the
treatment of cancer.
* The inhibition of aerobic glycolysis by a combination of alpha lipoic
acid and hydroxycitrate in Panaxea Synsergize eectively inhibits
tumour development (Baronzio et al., 2012)
Ingredients:
* Alpha Lipoic Acid
Hydroxycitric Acid 160 grams Powder
Silica
drdweber@panaxea.com 208 16/12/14
Panaxea Synsergize
* Eleven patients with advanced metastatic cancer from were
treated with per os 0.4 to 1.8 g of lipoic acid and 1.2 to 3 g of
hydroxycitrate during 2 to 21 months in addition to their normal
chemotherapeutic regimen. Side eects occurred in half of the
patients but were mild (grade 1-3) and limited to gastrointestinal
disorders that disappeared on using proton pump inhibitors or
decreasing the doses. Five patients were characterised by a partial
regression, 3 by a stable disease, and 3 by disease progression.
* Most of the patients receiving treatment for more than 6 months
displayed partial regression or stabilisation. In conclusion Baronzio
et al., (2012) found the results from these preliminary treatments
support that Synsergize can be used safely with various common
standard chemotherapeutic regimens.
drdweber@panaxea.com 209 16/12/14
Panaxea MEGA EGCH
* Additive and synergistic eects of EGCG when combined with
conventional cancer therapies have been proposed, and its
anti-inammatory and antioxidant activities have been
related to amelioration of cancer therapy side eects
(Lecumberri et al., 2013).
* Most cancers are believed to be initiated from and
maintained by a small population of cancer stem-like cells
(CSC) or tumour-initiating cells (TIC) that are responsible for
tumour relapse and chemotherapeutic resistance. EGCG, the
most abundant catechin in green tea, has been reported to
induce growth inhibition and apoptosis in some cancer cells
(Lin et al., 2012).
drdweber@panaxea.com 210 16/12/14
Chemotherapy Compounds
* Coenzyme Q10 and L-Carnitine protect the heart
* Vitamin E, L-Glutamine and B6 are neuro-protective
* Omega 3 for Cachexia
* Melatonin and IM1 mushroom extract protect the immune
system
* Coenzyme Q10 and multi-vitamin / mineral help with fatigue
* Vitamin D3 is a chemotherapy agonist
* Alpha Lipoic Acid is neuro-protective

drdweber@panaxea.com 211 16/12/14


Panaxea RTF (Radiotherapy)
Heat and Dampness with yin & qi Deciency
* Herba Hedyotiolis Diusae * Herba Agrimoniae Pilosae
(bai hua she she cao) (xian he cao)
* Tuber Asparagi * Tuber Curcumae (yu jin)
Cochinchinensis (tian dong) * Rhizoma Dioscoreae
Bulbiferae (huang yao zi)
* Fructus Ligustri Lucidi (nu
zhen zi) * Radix Astragali Membranacei
(huang qi)
* Sclerotium Poriae Cocos (fu * Radix Pseudostellariae (tai zi
ling) shen)
* Sclerotium Polypori Umbellati * Flos Lonicerae Japonicae (jin
(zhu ling) yin hua)
* Rhizoma Atractylodis * Radix Glycyrrhizae Uralensis
Macrocephalae (bai zhu) 212 (gan cao)
RTF2
Radiotherapy
* Astragalus membranaceous * Administration before
(huang qi) irradiation protected the
* Panax ginseng (ren shen, jejunal crypts (p < 0.0001),
ginseng) increased the formation of
* Angelica sinensis (dang gui) the endogenous spleen
colony (p < 0.05) and reduced
* Atractylodes macrocephala the frequency of radiation-
(bai zhu) induced apoptosis (Kim et al.,
* Bupleurum chinense (chai hu) 2002)
* Cimicifuga foetida (sheng ma)
* Glycyrrhiza uralensis (gan cao)
* Citrus reticulata (chen pi)
213
Radiotherapy Compounds
* L-glutamine * Digestive enzymes
* Curcumin * Jin Yin Hua
* Probiotics * Melatonin
* Alpha-lipoic acid * Silibinin
* Resveratrol * DIM/I3C
* SOD (LIFE) * EGCG
* Coenzyme Q10 * Vitamin A / Retinol

drdweber@panaxea.com 214 16/12/14


Panaxea POR
Post Operative Recovery
* Radix Astragali Membranacei * Sclerotium Poriae Cocos (fu ling)
(huang q)i * Pericarpium Citri Reticulatae (chen
* Radix Pseudostellariae (tai zi pi)
shen)
* Radix Angelicae Sinensis (dang * Fructus Crataegi processed (jiao
gui) shan zha)
* Rhizoma Polygonati (huang jing) * Massa Medica Fermentata
* Caulis Millettiae Reticulatae (ji processed (jiao shen qu)
xue teng) * Fructus Hordei Vulgaris Germinatus
* Radix Paeoniae Rubrae (chi processed (jiao mai ya)
shao) * Fructus Lycii (gou qi zi)
* Radix Rehmanniae Glutinosae * Radix Salviae Miltiorrhizae (dan
(sheng di) shen)
* Rhizoma Atractylodis
Macrocephalae (bai zhu) * Fructus Ligustri Lucidi (nu zhen zi)
*215 Herba Epimedii (yin yang huo)
Panaxea IM1 (Immune Function)
* Hericium erinaceus fruiting body * Maintains a correct balance
extract 14:1 (hou tou) between cellular and
* Maitake D fraction extract humoural immunity
* Reishi - Ganoderma lucidum
(broken spore extract)
* Astragalus membranaceus
(huang qi)
* Lentinula edodes/Shiitake extract
(xiang gu)
* Phellinus robiniae
* Polyporus umbellatus (zhu ling)
extract
* Trametes versicolor (yun zhi)
(extract) 216
Panaxea IM3 (Immune Function)
* Cordyceps sinensis (contains * Cellular immunity, cytotoxic,
extract puried apoptotic, activates cellular
polysaccharide) and humoural immune
* Ganoderma lucidum response
(contains extract Ganopoly
[30%]

drdweber@panaxea.com 217 16/12/14


Panaxea AV/AT
* Andrographolide treatment inhibited the proliferation of
dierent tumour cell lines. The compound exerts direct
anticancer activity on cancer cells by cell-cycle arrest at G0/G1
phase through induction of cell-cycle inhibitory protein p27
and decreased expression of cyclin-dependent kinase 4 (CDK4)
(Rajagopal et al., 2003).
* Immunostimulatory activity of andrographolide is evidenced
by increased proliferation of lymphocytes and production of
interleukin-2. Andrographolide also enhanced the TNF-
production and cluster of dierentiation (CD) expression,
resulting in increased cytotoxic activity of lymphocytes against
cancer cells (Kumar et al., 2004).
drdweber@panaxea.com 218 16/12/14
Panaxea AV/AT
* The polysaccharide fraction from Taraxii Herba, Taraxasterol
showed potent immuno-potentiating activities with anti-
tumour activities. The fraction having small amount of protein
inhibited the growth of solid tumour and increased peritoneal
exudate cells and immuno-organ weights (Jeong et al., 2009).
* Chlorogenic acid is a phenolic natural product isolated Flos
Lonicera, is an antioxidant, an inhibitor of the tumour
promoting activity of phorbol esters (Huang et al., 1988) and
its active principles possess wide pharmacological actions,
such as anti-inammatory, antibacterial, antiviral, and
antioxidative activities (Shang et al., 2011).

drdweber@panaxea.com 219 16/12/14


Panaxea AV/AT
* Andrographolide from * 3 isolates from commonly
Andographis paniculata used Chinese herbs
(chuan xin lian)
* Taraxasterol from
Taraxacum mongolicum (pu
gong yin)
* Chlorogenic Acid from Flos
Lonicera (jin yin hua)

drdweber@panaxea.com 220 16/12/14


Tamoxifen
* Tamoxifen induces cellular oxidative stress. Most breast
cancer, even those that are initially responsive to tamoxifen,
ultimately become resistant. The molecular basis for this
resistance, which in some patients is thought to involve
stimulation of tumour growth by tamoxifen, is unclear.
* Tamoxifen induces cellular oxidative stress, and because
changes in cell redox state can activate signalling pathways
leading to the activation of activating protein-1 (AP-1), which
in turn cause not only tamoxifen resistant breast cancer to
develop, but lead to tamoxifen activated breast cancer.

drdweber@panaxea.com 221 16/12/14


Panaxea BRC5
Tamoxifen Regulating Formula
* Mori Albae Fructus (sang * Rhizoma Anemarrhenae
shen) Asphodeloidis (zhi mu)
* Cortex Moutan Radicis (mu * Fructus Rosae Laevigatae (jin
dan pi) ying z)i
* Plastrum Testudinis (gui * Calyx Diospyros Kaki (zhi di)
ban) * Radix Polygoni Multiori (he
* Fructus Ligustri Lucidi (nu shou wu)
Zhen Zi * Radix Panacis Quinquefolii (xi
* Herba Ecliptae Prostratae yang shen)
(han lian cao)

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Jia Wei Xiao Yao San
* JWXYS is the most common Chinese medicine decoction co-
prescribed with tamoxifen (TAM) when breast cancer is
treated by hormonal therapy. Based on in vitro studies and in
vivo functional studies, there is no obvious interaction
between JWXYS and TAM (Chen et al., 2014).
* Among female breast cancer patients who had undergone
TAM therapy, Chinese herbal products (CHP) consumption
decreased the risk of subsequent endometrial cancer. Jia-
Wei-Xiao-Yao-San (Augmented Rambling Powder) and Shu-
Shu-Jing-Huo-Xue-Tang (Channel-Coursing Blood-Quickening
Decoction) were the two most commonly used CHPs (Tsai et
al., 2014).
drdweber@panaxea.com 223 16/12/14
Jia Wei Xiao Yao San
* JWXYS is often co-prescribed with tamoxifen when breast
cancer is treated by hormonal therapy (Lai et al., 2012). It is of
note that some of the herbs in JWXYS are able to upregulate
ERBB2 and ESR1 gene expression, while JWXYS alone does
not induce any signicant change in the expression of the
above-mentioned genes.
* Chui et al., (2014) attribute this to the fact that there are drug-
drug and drug-cell interactions between these components in
JWXYS's composition.
* Based on in vitro studies and in vivo functional studies, there
is no obvious interaction between JWXYS and Tam (Chen, et
al., 2014).
drdweber@panaxea.com 224 16/12/14
Jia Wei Xiao Yao San
* Radix Bupleuri (Chai Hu)
* Radix Angelicae Sinensis (Dang Gui)
* Radix Paeoniae Lactiorae (Bai Shao)
* Rhizoma Atractylodis Macrocephalae processed (Chao Bai Zhu)
* Sclerotium Poriae Cocos (Fu Ling)
* Radix Glycyrrhizae Uralensis (Zhi Gan Cao)
* Rhizoma Zingiberis Ocinalis Recens (Sheng Jiang)
* Cortex Moutan Radicis (Mu Dan Pi)
* Fructus Gardeniae Jasminoidis (Zhi Zi)
* Herba Menthae Haplocalycis (Bo He)
drdweber@panaxea.com 225 16/12/14
Shu Gan Liang Xue
(SEEMs)
* Shu-Gan-Liang-Xue (SGLX) a classic formula was tested on endocrine
therapy- associated hot ashes symptom in breast cancer patients.
* For hot ashes symptom, in Chinese herbs decoction administration
group, 21.9% reported symptom disappeared, 68.7% reported symptom
alleviated, 9.4% reported symptom not changed; in endocrine therapy
alone group, 17.9% reported symptom disappeared, 46.4% reported
symptom alleviated, 35.7% reported symptom not changed (Xue, Sun,
Li, 2011).
* SGLX decoction, having synergistic eect on TAM, can reduce serum
hormone level and alleviate the endometrial hypertrophy side eect
of TAM. The results suggest that SGLXD is a potential dual aromatase-
sulfatase inhibitor by simultaneously down-regulating the expressions
of CYP19 and STS in MCF-7 and T47D cells (Fu & Li, 2011).
Shu Gan Liang Xue
* SGLX showed dose-dependent inhibitory eect on the
proliferation of ZR-75-1 cells with IC50 value of 3.40 mg/mL. It also
suppressed the stimulating eect on cell proliferation of
testosterone and oestrogen sulfates (E1S). Oral administration of
6 g/kg of SGLX for 25 days resulted in a reduction in tumour
volume in non-ovariectomized and ovariectomised nude mice.
* Results suggested that SGLX showed anti-tumour eect on
breast cancer cells both in vitro and in vivo. The anti-tumour
activity of SGLXD is related to inhibition of aromatase and STS
gene via decreasing their expression. SGLX may be considered as
a novel treatment for ER positive breast cancer (Zhou et al.,
2014).
Shu Gan Liang Xue
* Shu-Gan-Liang-Xue Decoction (SGLX), a Chinese herbal formula,
acts as a selective oestrogen enzyme modulators (SEEMs) agent
by down-regulating the expression of Steroid sulfatase (STS) in
the levels of transcript and enzymatic activity.
* In view of the aforementioned characteristics, SGLX could serve
as a novel therapeutic treatment to combat hormone-
dependent breast cancer (HDBC) (Zhang & Li, 2010).
* SEEMs: clomifene, femarelle, ormeloxifene, raloxifene,
tamoxifen, toremifene, lasofoxifene, ospemifene
Panaxea SEEMs (SGLX)
* Radix Lithospermi (zi cao gen)
* Cortex Moutan Radicis (mu dan pi)
* Fructus Schisandrae Chinensis (wu wei zi)
* Radix Paeoniae Alba (bai shao)
* Radix Bupleuri Chinensis (chai hu)
* Radix Curcumae Wenyu-jin (yu jin)
* Radix Cynanchi Atrati (bai wei)

drdweber@panaxea.com 229 16/12/14


Tamoxifen Paper
* Drug Herb Interactions: Tamoxifen
* http://www.elotus.org/content/drug-herb-interactions-
tamoxifen-mm-van-benschoten-omd
* M.M. Van Benschoten: mmvbs8813@gmail.com

drdweber@panaxea.com 230 16/12/14


Multi-Drug Resistance
* MDR is dened as insensitivity of cancer cells to cytotoxic and
cytostatic actions of a number of structurally and functionally
unrelated drugs. Cancer cells are intrinsically resistant to anti-
cancer agents because of genetic and epigenetic
heterogeneity.
* Also, there are some host factors which include poor
absorption, rapid metabolism and excretion that can result in
low serum drug levels. The mechanisms include alteration in
the expression of proteins involved in the apoptotic signalling
such as p53, Bcl2 family of proteins

drdweber@panaxea.com 231 16/12/14


Multi-Drug Resistance
* Multidrug-resistance (MDR) is the chief limitation to the
success of chemotherapy. According to the National Cancer
Institute, multidrug-resistance is a phenomenon where cancer
cells adopt to anti-tumour drugs in such a way that makes the
drugs less eective. Studies have shown that 40% of all human
cancers develop MDR.
* Deaths due to cancer occur in most of the cases when the
tumour metastasises. Chemotherapy is the only choice of
treatment in metastatic cancer, and MDR limits that option.
* Chemotherapy kills drug-sensitive cells, but leaves behind a
higher proportion of drug-resistant cells. As the tumour begins
to grow again, chemotherapy may fail because the remaining
tumour cells are now resistant. 232 16/12/14
Multi-Drug Resistance
* Ginsenosides
* Rg3 reversed multi-drug resistance and restored the sensitivity of
resistant KBV20 cell line to various anticancer drugs. Increased animal
life span in an in vivo MDR model in a dose-independent manner (Kim SH
et al, 2003; Yue et al, 2006).
* Combination of puried saponins containing Rb1, Rb2, Rc, Rd, Re and Rg1
reversed MDR (Liu et al, 2008; Si & Tien, 2005)
Quercetin/Kaempferol
* Quercetin is less potent than kaempferol but more eective than
genistein and daidzein in reversing MDR (Kioka et al, 1992).
* Quercetin reverses MDR through action on mitochondrial membrane
potential and the induction of apoptosis (Kothan et al, 2004)
* Puerarin
* Down-regulates MDR1 expression via nuclear factor -B and CRE (cAMP
response element) transcriptional activity (Hien et al, 2010)
233 16/12/14
Multi-Drug Resistance
* Curcumin
* Enhances sensitivity to vincristine by the inhibition of P-gp in
SGC7901/VCR cell line (Chang et al, 2006).
* Curcumin derivatives reversed MDR by inhibiting P-gp eux (Tang
et al, 2005)
* Curcumin derivatives reversed MDR by inhibiting P-gp eux
(Limtrakul et al, 2004).
* Honokiol
* Down-regulates expression of P-glycoprotein at mRNA and
protein levels in MCF-7/ADR, a human breast MDR cancer cell line
(Xu et al, 2006)
* Quercetin
* Inhibits overexpression of P-gp mediated by arsenite (Kioka et al,
1992). 234 16/12/14
Blood Stasis & qi Stagnation

Pain

drdweber@panaxea.com 235 16/12/14


Herbal Hot Compress Treatment
* Chuan Wu (Radix Aconiti) 100g * Advanced breast cancer
* Xi Xin (Herba Asari) 50g pain poultice
* Qing Pi (fructus citri reticulatae * All herbs are ground into
immaturus) 50g powder, mixed with vinegar
* Chuan Xiong (Rhizoma Ligustici to make a paste, applied
Chuanxiong) 50g directed on the lesion, and
then xed with plastic
* Ma Huang (Herba Ephedrae) 50g material.
* Bing Pian (Borneolum
* Apply hot compresses for
Syntheticum) 50g 1030 min to alleviate the
* Zhang Nao (camphor) 50g pain
* Gan Cao (Radix Glycyrrhizae) 50g
236 16/12/14
Panaxea Free Movement
* Gentiana macrophylla (qin * Notopterygium incisum
jiao) (qiang huo)
* Salvia miltorrhiza (dan shen) * Angelica sinensis (dang gui)
* Panax notoginseng (san qi) * Citrus aurantium (zhi ke)
* Storax Styrax (su he xiang) * Tribulus terrestris (bai ji li)
* Ligusticum Chuanxiong * Cyperus rotundus (xiang fu)
(chuan xiong) * Stephania tetrandra (fen fang
* Prunus persica (tao ren) ji)
* Carthamus tinctorius (hong * Achyranthes bidentata (chuan
hua) niu xi)
* Myrrha (mo yao) * Manganese
237 16/12/14
Jing Huo Xue Tang
* Radix Ledebouriellae (fang * Pericarpium Citri Reticulatae
feng) (chen pi)
* Radix Notopterygium (qiang * Rhizoma Ligustici Chuanxiong
huo) * Semen Persicae (tao ren)
* Radix Angelica Dahuricae (bai * Radix Cyathulae (chuan niu xi)
zhi) * Radix Angelicae Sinensis (dang
* Radix Rehmanniae (sheng di) gui)
* Radix Gentianae (long dan cao) * Radix Paeoniae Alba (bai shao)
* Poriae Cocos (fu ling) * Radix Stephaniae Tetandrae
* Radix Clematidis (wei ling xian) (han fang ji)
* Rhizoma Atractylodes lancea * Radix Glycyrrhizae (gan cao)
(cang zhu)
238 16/12/14
Zao Jiao Ci Ju Pi Mi Yin
* Zao Jiao Ci (Spina Gleditsiae) * These formulation are to
30g invigorate the Blood,
* Qing Pi (Pericarpium Citri dissipate Blood Stasis,
Reticulatae Viride) 20g promote movement of qi and
* Chen Pi (Pericarpium Citri alleviate pain.
Reticulatae) 20g * They are benecial for breast
* Wang Bu Liu Xing Zi (Semen cancer patients with varying
Vaccariae 20g symptoms of Stagnant qi,
Stasis of Blood, and pain.
* Yu Jin (Radix Curcumae) 15g
* honey 30g

drdweber@panaxea.com 239 16/12/14


Cautions & Contraindications

drdweber@panaxea.com 240 16/12/14


Cautions & Contraindications
* Thirteen single herbal extracts and ve compound recipes
were found to increase either ERBB2 or ESR1 luciferase
activity.
* Si Wu Tang, Guan Xin Yin, and Suan Zao Ren Tang were found
to increase either HER2 or ER protein expression. In
addition, Ligusticum chuanxiong was shown to have a great
eect on ERBB2 gene expression and synergistically with
oestrogen to stimulate MCF-7 cell growth.
* Si Wu Tang reverses the antiproliferative eects induced by
tamoxifen, including tumour weight, tumour volume,
increased ER expression, and N-cadherin expression (Chui et
al., 2014)
drdweber@panaxea.com 241 16/12/14
Cautions & Contraindications
* Silymarin is a mixture of polyphenolic avonoids isolated
from milk thistle (Silybum marianum) with anticancer
activities reported for several organ sites.
* The results showed that dietary silymarin increased the
plasma concentration of free and total silibinin, a major
component of silymarin, in a dose-dependent manner in the
rat, but did not decrease either mammary tumour (MT)
incidence or number. Instead silymarin modestly increased
the number of 1-methyl-1-nitrosourea (MNU)-induced MTs in
rats (Malewicz et al., 2006).

drdweber@panaxea.com 242 16/12/14


This is only an introduction to the complex and artful
application of Chinese herbal medicine to breast cancer

Thank You

drdweber@panaxea.com 243 16/12/14


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