Phenoxodiol--an isoflavone analog--induces apoptosis in chemoresistant ovarian cancer cells.
Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. In this study we characterize the cytotoxic effect of phenoxodiol, a synthetic anticancer drug analog of genestein, and demonstrate the mechanism of action by which phenoxodiol affects the components of the Fas apoptotic pathway on ovarian cancer cells. Primary ovarian cancer cells, isolated from ascitic fluids of ovarian cancer patients, resistant to conventional chemotherapy, undergo apoptosis following phenoxodiol treatment. This effect is dependent upon the activation of the caspase system, inhibiting XIAP, an inhibitor of apoptosis, and disrupting FLICE inhibitory protein (FLIP) expression through the Akt signal transduction pathway. We suggest that phenoxodiol is an efficient inducer of cell death in ovarian cancer cells and sensitizes the cancer cells to Fas-mediated apoptosis. We identified FLIP and XIAP signalling pathways as key factors regulating the survival of ovarian cancer cells. These findings demonstrate a novel nontoxic drug that controls FLIP/XIAP function and has the potential to eliminate tumor cells through Fas-mediated apoptosis.
Department of Obstetrics and Gynecology, Yale University, School of Medicine, New Haven, CT 06520, USA.
Marijke
M
Kamsteeg
Thomas
T
Rutherford
Eva
E
Sapi
Bozena
B
Hanczaruk
Shoreh
S
Shahabi
Maryann
M
Flick
David
D
Brown
Gil
G
Mor
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000502:physiology; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007529:Isoflavones / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010636:Phenols / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor / Q000378:metabolism
D000970:Antineoplastic Agents; D001578:Benzopyrans; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D007529:Isoflavones; D008562:Membrane Glycoproteins; D010636:Phenols; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D019014:fas Receptor; C471183:phenoxodiol; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases