Phenoxodiol, A New Approach For The Treatment of Ovarian Cancer.
Flavonoids
are one of the principal plant hormones and are known to possess diverse
functional roles including the regulation of plant apoptosis and cell
cycle kinetics. A number of plant flavonoids show similar functional
effects in animals and may be effective in inducing mitotic arrest
and apoptosis. In particular, genestein, quercetin and flavopiridol
have been shown to exert effects on human cancer cells (23) (24) suggesting
that this class of molecules may offer novel approaches to cancer
therapy. Preliminary studies involving a number of flavonoid derivatives
showed that phenoxodiol (2H-1-Benzopyron-7-0,3-(hydroxy phenyl)) inhibits
cellular proliferation of a wide range of human cancer cell lines
including leukemia, breast and prostate carcinomas, and is 5-20 times
more potent that genestein. Phenoxodiol was selected for its greater
in vitro anti-cancer potency against human cancer cells and for its
specific ability to (a) down-regulate the production of sphingosine-1-phosphate,
an essential secondary messenger in the signal transduction processes
involved in cell survival and over-expressed in many human cancers
including ovarian cancer, (b) down-regulate the production of anti-apoptotic
proteins including c-FLIP and XIAP, and (c) up-regulate the production
of pro-apoptotic proteins such as Bax.
Origins of Phenoxodiol. Phenoxodiol is a pharmacophore
of genestein based on a central diphenylpropane (or di-phenolic)
ring structure. One of the functions of genestein in plants is to
regulate gene transcription in both the plant and symbiotic bacteria
(25). Many flavonoids also show biological activity in mammalian
cells, regulating functions such as cell cycle kinetics and cell
survival. Genestein appears to be among the most active flavonoid
in this regard. Genestein is a potent inhibitor of protein tyrosine
kinases (26),(27) and DNA topoisomerases I and II (28). Their effect
is to induce mitotic arrest of human cancer cells in G2/M5 terminal
differentiation of cancer cells (29, 30), and apoptosis (31). Genestein
also displays a range of other biological effects including inhibition
of angiogenesis (32), and promotion of cancer cell adhesion (33).
Genestein displays anti-cancer activity in vitro against various
types of human and animal cancers including melanoma (29), leukemia
(28-30), breast cancer (34-36), gastrointestinal cancers (36), prostate
cancer (37) and neuroblastoma, Ewing’s sarcoma and rhabdomyosarcoma(38).
Phenoxodiol
and Ovarian cancer. Anticancer agents induce apoptosis in normal
tissues as well as in tumors. The development of new treatments
for ovarian cancer that can specifically restore apoptosis in cancer
cells without affecting normal cells is a crucial objective. We
studied the effects of phenoxodiol on ovarian cancer cells with
the objective to modulate the blockers of apoptosis and sensitize
the cancer cells to apoptotic stimuli. Phenoxodiol has proven to
fulfill these objectives both in vitro and in vivo (3)
For more details on Phenoxodiol and ovarian cancer research see
the following Power Point presentation:
Phenoxodiol.ppt
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