Combination Of Fty720 And Tamoxifen Inhibits Drug-Resistant Ovarian Cancer Cell Proliferation

Abstract Despite satisfactory initial responses to frontline therapies that combine surgical debulking with platinum based chemotherapy, virtually all women with advanced ovarian cancer relapse with drug resistant disease. There is a critical need to identify alternative, effective therapies. Previously, we used patient derived xenograft (PDX) models of ovarian cancer in mice to identify the sphingosine1 phosphate (S1P) pathway as one of the pathways most affected by two agents frequently used to treat ovarian cancer, carboplatin and paclitaxel. The S1P pathway contributes to multiple biological processes recognized as essential for tumor development, and aberrations in sphingolipid metabolism have been directly correlated with advanced disease and with resistance to chemotherapy and radiation. Further, recent studies indicate that tamoxifen may counteract drug resistance mechanisms through modulation of sphingolipid metabolism, specifically through inhibition of the ceramide converting enyzmes acid ceramidase and glucosylceramide synthase. Therefore, we evaluated the efficacy of modulating S1P metabolism using the sphingosine analog FTY720 and tamoxifen as an approach to inhibit the proliferation of drug-resistant ovarian tumor cells. We used alamarBlue cell proliferation assays to compare the anti-proliferative effect of FTY720 and tamoxifen with the effect of each drug as a single agent. FTY720 + tamoxifen synergistically decreased the cell viability of 3/3 ovarian cancer cell lines: estrogen receptor alpha (ERα) positive SKOV3.TR (taxane resistant), ERα negative A280.cp20 (platinum resistant) and HeyA8.MDR (taxane-platinum resistant). The combination also increased levels of apoptosis as reflected by Annexin V staining and cleaved caspase 3 levels. Further, administration of 5mg/kg i.p. FTY720 + 20mg/kg p.o. tamoxifen daily for 21 days to PDX-bearing mice demonstrated that FTY720 + tamoxifen suppressed tumor growth by ~60% compared to vehicle controls. Notably, immunohistochemical staining of tumors harvested from treated mice showed that the combination decreased expression of the proliferation marker Ki-67 and increased expression of apoptosis indicators ceramide and cleaved caspase 3 to a greater degree than in tumors exposed to either drug alone. We conclude that FTY720 + tamoxifen merit further investigation as potentially effective agents for the treatment of drug-resistant ovarian cancer. Citation Format: Kelly Marie Kreitzburg, Charles N. Landen, Tracy Gamblin, Rebecca Arend, Ronald Alvarez, Karina Yoon. Combination of FTY720 and tamoxifen inhibits drug-resistant ovarian cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4115. doi:10.1158/1538-7445.AM2017-4115