|Traditional herbal therapies such as Traditional Chinese Medicine
(TCM) are increasingly used in the treatment of diseases including
cancer. These medicines are either a single herb based or frequently
made of multiple herbs, based on the combinational benefits of the
herbal medicine. The formulations are supported by traditional
sometimes ancient theories, others based on practical experience. This
has frequently made the understanding of how the medicine(s) works
(or potential mechanism) a challenge. However, some of the herbal
medicine(s) that have demonstrable and reproducible clinical benefits
attracted attention to explore mechanism(s) of action, attempt to
separate the active ingredient(s) from the herbs. Artemisinin perhaps
serves a good example. The compound is extracted and purified from
an anti-malaria Chinese herb QingHao in nineteen seventies and
found to be a highly effective anti-malaria medicine. It is now used
throughout the world since nineteen nineties as one of the first line
treatment for malaria . Another example is the discovery of Taxol
from Western Yew barks in the nineties, which (including its
derivatives) is now one of the popular frontline drugs for cancer
|However, a few other medicines that have clinical benefits yet clear
mechanism(s) and/or active ingredient(s) are yet to be identified. A
good example is a TCM formula known as Qili QiangXin which was
found to be highly effective in treating heart failure . The clinical
effective formulae/herbs may prove to be a fertile ground in search for
new medicine and new approaches. Another example is a TCM based
treatment, known as HuangQiTang which has been reported with
beneficial effects for patients with cancer in meta analysis from
published work . Searching for alternative methods in treating
cancer and mechanisms of those known to work have been long and
continued efforts, a recent example being the Get to Know Cancer
Network which drew a large group of international experts in
searching for options including low toxic naturally occurring remedies
in treating cancer (www.gettingtoknowcancer.org) .
|YangZheng XiaoJi and Cancer Treatment
|We have recently come cross a TCM formula, known as YangZheng
XiaoJi, which is a prescription only medicine (POM) used for patients
with malignant conditions. The medicine formula is made of 16 TCM
herbs and has been approved in China for use in patients with cancer
including liver and lung cancers . It appears to have an implication
in other conditions such as gastric dysplasia. Clinically, the medicine
has been found to be able to increase the sensitivity of chemotherapy
and at the same time reduce the side effects associated with
chemotherapy including weight loss and bone marrow suppression. A
recent meta analysis of over 2,000 patients has shown that the medicine has very low side effects . Beyond the clinical efficacy and
observed biochemical and immunological changes with the patients,
there have however been little reports on how the medicine works, at a
cellular, molecular or genetic level. We have recently taken an interest
in this medicine and explored how it might work in the cells with an
emphasis at signalling transduction.
|YangZheng XiaoJi Extract and Angiogenesis in
|Given that the medicine was formulated based on the Collateral
Disease theory in Chinese medicine, which strongly implicates a
pivotal role of endothelial cells in disease, we first tested the medicine
on vascular endothelial cells and angiognesis . It came to our
surprise that the medicine has shown a profound effect on
angiogenesis both in vitro and in vivo. In vitro, it markedly inhibited
the migration and tubule formation of vascular endothelial cells and
more interestingly reduced the phosphorylation of FAK (focal
adhesion kinase), a kinase central to cell-matrix, cell migration and
intracellular signalling. Subsequently, we have also found that the
medicine also inhibits the activation of FAK in malignant cells
including osteosarcoma .
|The Broader Effect of the Medicine on Cancer Cells
|YangZheng XiaoJi appears to have a direct effect on cancer cells.
For example, a series of cancer cell lines from different tumour types
have been shown to respond to the medicine. These cells are
originated from human lung cancer, gastrointestinal cancer,
pancreatic cancer, endocrine related (namely breast and prostate)
cancers and as indicated early, from osteosarcoma [8-10]. The
profound response of these cancer cells to YangZheng XiaoJi appears
to be cell adhesion and cell migration, and to some degree cell growth.
The change in cell adhesion is probably not so surprising, given the
observed effect of the medicine on focal adhesion kinase (FAK) in
endothelial cells. These studies have further demonstrated that
pathways including the AKT pathway, the SHH (Sonic Hedgehog),
SRC pathways and HGFR-EGFR transactivation [8-11], which are
widely involved in cell migration and cell growth, are responded to the
medicine. For example, in a lung xenograft tumour model, the levels of
SHH and SMO were reduced in response to the treatment with
YangZheng XiaoJi .
|Potential Implications in Peritoneal Metastasis of
|One of the recent experimental findings with YangZheng XiaoJi is
its potential in interfering the interaction between tumour cells and peritoneal mesothelial interactions. The studies have demonstrated
that it is able to reduce the peritoneal metastasis from various
gastrointestinal and ovarian cancers [13,14]. This role of YangZheng
XiaoJi was thought to be by blocking CD44-Hyaluronan interactions
via its effect on the SRC pathway, downstream of CD44 [13,14].
|YangZheng Xiaoji and a Wider Therapeutic
|Although the medicine has been so far given to patients in
combination with traditional chemotherapy and radiotherapy, one
would argue that the impact of the medicine on multiple signalling
pathways may open a new front when considering combined therapies
with neoadjuvent agents including kinase inhibitors. Indeed,
experimental data from in vivo models have shown that the medicine
is able to have a synergistic effect with SHH inhibitor, cMET inhibitor
and FAK inhibitor [8,11,12]. It is plausible to suggest new clinical
studies/trials by combining YangZheng XiaoJi and the respective
|Thus, YangZheng XiaoJi has been shown to influence a number
of signalling pathways in cancer and endothelial cells. This is
interesting as targeting multiple signalling pathways in cancer
treatment has been widely proposed [15-17] and that combinational
therapies using multiple signalling inhibitors have been trialled
presently [18-20]. It is thus possible that a herbal medicine or herbal
formula such as YangZheng XiaoJi targets multiple pathways in cancer
in a clinical senario and thus delivers clinical benefits. Of course,
future work will contest if this is sensible and viable.
|This short editorial aims to provide an overview of the trails of
development and findings of a traditional formula in cancer treatment.
It is also aimed to excite more interest in researching into traditional
medicine that has shown clinical promise. Presently and for the
particular medicine discussed in this editorial, one would anticipate a
tremendous challenge ahead, including identification of active
ingredient(s) or the mixture of active ingredient (s), if further
reduction to the size of the formulation can be made, extending the
delivery route from oral to other routes to allow room for dosage
variation, common tasks for most herbal based medicines. Targeting
multiple pathways in cancer is coming and that traditional medicine
may well have a role to play here.
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