title: Combination of FTY720 with cisplatin exhibits antagonistic effects in ovarian cancer cells: role of autophagy.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
authors.lastname: Dai
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Qi
authors.forename: Wen
authors.initials: W
authors.lastname: Di
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004336:Drug Antagonism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011409:Propylene Glycols / Q000494:pharmacology*; D034741:RNA, Small Interfering; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D034741:RNA, Small Interfering; C025946:3-methyladenine; D000068876:Fingolimod Hydrochloride; D000225:Adenine; D013110:Sphingosine; D002945:Cisplatin