Combination of FTY720 with cisplatin exhibits antagonistic effects in ovarian cancer cells: Role of autophagy

Zhang,Ning; Dai,Lan; Qi,Yanfei; Di,Wen; Xia,Pu

doi:10.3892/ijo.2013.1906

Combination of FTY720 with cisplatin exhibits antagonistic effects in ovarian cancer cells: Role of autophagy

Authors:
- Ning Zhang
- Lan Dai
- Yanfei Qi
- Wen Di
- Pu Xia
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Affiliations: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China, Signal Transduction Program, Centenary Institute, Sydney Medical School, University of Sydney, Australia
Published online on: April 17, 2013 https://doi.org/10.3892/ijo.2013.1906
Pages: 2053-2059

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Abstract

Combination therapy with different anticancer drugs has been proven to be an effective strategy for the treatment of various types of cancers, including ovarian cancer. We have previously reported that FTY720 exhibited potent cytotoxic effects in ovarian cancer cells through the necrotic pathway, which differs from the killing effect of cisplatin (CDDP). In the present study, we report that the combination of FTY720 with CDDP yields an unexpected antagonistic effect towards the cytotoxicity of CDDP in a variety of ovarian cancer cell lines, including both CDDP-sensitive and -resistant cells. The antagonistic activity of FTY720 appears ascribable to its effect in autophagy induction. A significant increase in baseline autophagy was observed in CDDP-resistant ovarian cancer cells, compared with the sensitive cells. Blockade of autophagy by either a pharmacological inhibitor (3-MA) or siRNA-mediated knockdown of autophagic gene expression enhances CDDP-induced apoptotic cell death. Notably, by inhibiting autophagy, 3-MA can convert the combination of FTY720 with CDDP from an antagonistic into an additive effect towards killing ovarian cancer cells. Collectively, the findings suggest that a combination of an autophagy regulator with the CDDP-based regime could effectively modulate its efficacy for the treatment of ovarian cancer.

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