Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells.
BACKGROUND
Previously, it was demonstrated that phenoxodiol induces apoptosis in epithelial ovarian carcinoma (EOC) cells and that it is capable of sensitizing these cells to Fas-mediated apoptosis. The objectives of this study were to determine whether phenoxodiol can also act as chemosensitizer to chemotherapeutic agents and to characterize the molecular mechanism behind its sensitizing effect.


METHODS
Ten EOC cell lines were used in this study. The effect of phenoxodiol on the inhibitory concentration 50% (IC50) of carboplatin, paclitaxel, and gemcitabine was determined by the CellTiter 96 Assay. The in vivo effect of combination treatments with phenoxodiol and the above-mentioned agents was determined in animal xenograft models. Apoptosis was measured using the Caspase-Glo Assay and the apoptotic cascade was characterized by Western blot analyses.


RESULTS
The results showed that phenoxodiol is able to sensitize EOC cells to carboplatin, paclitaxel, and gemcitabine both in vitro and in vivo. In addition, it was demonstrated that phenoxodiol is capable of inducing apoptosis by: 1) the activation of the mitochondrial pathway through caspase-2 and Bid signaling, and 2) the proteasomal degradation of the anti-apoptotic protein XIAP.


CONCLUSIONS
Understanding the components of the apoptotic pathway activated by phenoxodiol, which allows it to sensitize EOC cells to chemotherapeutic agents, will provide valuable information on the characteristic mode of action of a chemosensitizer. This will help in the identification of novel drugs and in the design of better strategies for combination therapy in patients with recurrent ovarian carcinoma.
Alvero
Ayesha B
AB
Department of Obstetrics & Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
O'Malley
David
D
Brown
David
D
Kelly
Graham
G
Garg
Manish
M
Chen
Wei
W
Rutherford
Thomas
T
Mor
Gil
G
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016190:Carboplatin / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology*; D053143:Caspase 2; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D051379:Mice; D010051:Ovarian Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D007529:Isoflavones; D003841:Deoxycytidine; C471183:phenoxodiol; D016190:Carboplatin; D053143:Caspase 2; D020169:Caspases; D046988:Proteasome Endopeptidase Complex; D017239:Paclitaxel; D000093542:Gemcitabine