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Marshall Edwards' Phenoxodiol and Novogen's NV-128 Display Divergent Mechanisms of Action but Potent Synergistic Anti-Cancer Activity When Used in Combination
| Source: Novogen, Limited
NEW CANAAN, CT and SYDNEY, AUSTRALIA--(Marketwire - October 30, 2008) - Pre-clinical studies
presented at the 9th International Conference on Membrane Redox Systems in
Wellington New Zealand this week demonstrate that Novogen's NV-128 (a novel
mTOR inhibitor), when used in combination with the Marshall Edwards, Inc.'s
Phase III anti-ovarian cancer drug, phenoxodiol, produces potent
synergistic anti-cancer activity against non-small cell lung carcinoma cell
lines (NSCLC). Importantly, the synergistic cytotoxicity observed between
NV-128 and phenoxodiol was superior to the synergy observed between NV-128
and paclitaxel against NSCLC. These data were presented by Dr. David
Brown, Program Manager (Cancer Biology), Novogen.
"In NSCLC targets, these two drugs in combination produced an anti-cancer
effect superior to that achieved with either drug alone or in combination
with current approved anti-cancer cytotoxic drugs. The potential for
improved efficacy, coupled with the safety profile of these novel drugs,
suggests the potential for clinical benefits in lung cancer patients which
cannot be achieved with current standard of care drugs," Dr. Brown said.
Phenoxodiol is being developed as a therapy for late-stage, chemoresistant
prostate and ovarian cancers. It is a novel-acting drug that inhibits key
pro-survival signaling pathways operating via sphingosine-1-phosphate and
Akt. Inhibition of these pathways leads to prevention of phosphorylation
of key anti-apoptotic proteins such as XIAP and FLIPs. Loss of activity of
these proteins restores the ability of chemoresistant tumor cells to
undergo caspase-mediated apoptosis in response to chemotherapy. The
putative molecular target for phenoxodiol is a surface oxidase which is
preferentially expressed on cancer cells and is linked to the expression of
pro-survival pathways in these cells. The ability of the drug to bind
preferentially to cancer cells rather than normal cells is reflected in its
high safety profile in clinical use.
In contrast to phenoxodiol, NV-128 does not induce caspase-mediated
apoptosis, a death mechanism which is often non-functional in
chemoresistant cancer cells due to accumulated mutations in tumor
suppressor/promoter genes and over-expression of anti-apoptotic proteins.
Rather, NV-128 uncouples the akt-mTOR-P70S6K signal transduction cascade
which has a key role in driving protein translation and uncontrolled cancer
cell proliferation. Further, NV-128 induces mitochondrial depolarization
via a novel pathway involving the autophagy protein Beclin-1 and Bcl-2,
thereby resulting in endonuclease G translocation to the nucleus and cell
death. Importantly, when NV-128 is used in combination with phenoxodiol,
XIAP is degraded in these cells allowing the caspase-mediated apoptosis
cascade to be engaged in addition to NV-128-endonuclease G mediated
apoptosis resulting in two pathways to cell death.
"These data provide direct evidence that while invoking discrete modes of
cell death, NV-128 and phenoxodiol can be used synergistically to force the
convergence of caspase-mediated and caspase-independent cell death pathways
to drive overall cell death," said Dr. Brown.
About Novogen Limited:
Novogen Limited (ASX : NRT ) (NASDAQ : NVGN ) is an Australian biotechnology
company that has patented isoflavone technology for the treatment and
prevention of degenerative diseases and disorders. Over the past ten
years, Novogen has conducted the largest and most comprehensive isoflavone
clinical testing programs in the world. Novogen is involved in drug
discovery and product development for a range of degenerative disorders
including cancer, cardiovascular diseases and inflammatory diseases. The
Company coordinates an international clinical research and development
program with external collaborators, hospitals and universities. For more
information, visit www.novogen.com.
About Marshall Edwards, Inc:
Marshall Edwards, Inc. (NASDAQ : MSHL ) is majority owned by Novogen. It as
a specialist oncology company focused on the clinical development of novel
anti-cancer therapeutics derived from the flavonoid technology platform.
This platform has generated a number of novel anti-cancer compounds
characterized by broad ranging activity against a range of cancer cell
types with few side effects. The combination of anti-tumor cell activity
and low toxicity is believed to be a result of the ability of these
compounds to target an enzyme present on the surface of cancer cells,
thereby inhibiting the production of pro-survival proteins within the cell.
Marshall Edwards, Inc. has licensed rights from Novogen Limited (NASDAQ : NVGN ) to bring three oncology drugs -- phenoxodiol, triphendiol and NV-143
-- to market globally. The Company's lead investigational drug,
phenoxodiol, is in a Phase III multinational multi-centered clinical trial
for patients with recurrent ovarian cancer. More information on the trial
can be found at http://www.OVATUREtrial.com.
Under U.S. law, a new drug cannot be marketed until it has been
investigated in clinical trials and approved by the FDA as being safe and
effective for the intended use. Statements included in this press release
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