The first two authors contributed equally to this study.
Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells
Article first published online: 30 DEC 2005
Copyright © 2005 American Cancer Society
Volume 106, Issue 3, pages 599–608, 1 February 2006
How to Cite
Alvero, A. B., O'Malley, D., Brown, D., Kelly, G., Garg, M., Chen, W., Rutherford, T. and Mor, G. (2006), Molecular mechanism of phenoxodiol-induced apoptosis in ovarian carcinoma cells. Cancer, 106: 599–608. doi: 10.1002/cncr.21633
- Issue published online: 20 JAN 2006
- Article first published online: 30 DEC 2005
- Manuscript Accepted: 30 AUG 2005
- Manuscript Revised: 25 AUG 2005
- Manuscript Received: 29 JUN 2005
- National Cancer Institute (NCI). Grant Number: R01-CA92435-01
- Mr. Nicholas F. Brady and the Jeffrey Mayersohn Foundation
- ovarian carcinoma;
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.
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.
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.
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.