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Molecular mechanism of phenoxodiol‐induced apoptosis in ovarian carcinoma cells
Author(s) -
Alvero Ayesha B.,
O'Malley David,
Brown David,
Kelly Graham,
Garg Manish,
Chen Wei,
Rutherford Thomas,
Mor Gil
Publication year - 2005
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.21633
Subject(s) - xiap , chemosensitizer , apoptosis , carboplatin , paclitaxel , cancer research , gemcitabine , in vivo , inhibitor of apoptosis , ovarian cancer , pharmacology , medicine , cancer , caspase , chemistry , cisplatin , biology , in vitro , programmed cell death , chemotherapy , cytotoxicity , biochemistry , microbiology and biotechnology
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% (IC 50 ) 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. CONCLUSION 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. Cancer 2006. © 2005 American Cancer Society.