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Phenoxodiol – an isoflavone analog – induces apoptosis in chemoresistant ovarian cancer cells

Oncogene volume 22, pages 2611–2620 (2003)Cite this article

Abstract

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.

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Acknowledgements

We thank Sofya Rodov for technical assistance and Dr Reena Jain from the Department of Pathology for analysis of the cells. This work was supported in part by a grant from the NCI R01-CA92435-01 and NICHD RO1 HD37137-01A2 to GM.

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  1. David Brown: Marshal Edwards, Inc North Ryde, Australia

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Yale University, School of Medicine, New Haven, CT, USA

    Marijke Kamsteeg, Thomas Rutherford, Eva Sapi, Bozena Hanczaruk, Shoreh Shahabi, Maryann Flick, David Brown & Gil Mor

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  1. Marijke Kamsteeg
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  2. Thomas Rutherford
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Correspondence to Gil Mor.

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Kamsteeg, M., Rutherford, T., Sapi, E. et al. Phenoxodiol – an isoflavone analog – induces apoptosis in chemoresistant ovarian cancer cells. Oncogene 22, 2611–2620 (2003). https://doi.org/10.1038/sj.onc.1206422

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Keywords

  • phenoxodiol; apoptosis; XIAP; ovarian cancer; Fas

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