FTY720 enhances the anti-tumor activity of carboplatin and tamoxifen in a patient-derived xenograft model of ovarian cancer

Abstract

Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Although most patients respond to frontline therapy, virtually all patients relapse with chemoresistant disease. This study addresses the hypothesis that carboplatin or tamoxifen + FTY720, a sphingosine analogue, will minimize or circumvent drug-resistance in ovarian cancer cells and tumor models. In vitro data demonstrate that FTY720 sensitized two drug-resistant (A2780. cp20, HeyA8. MDR) and two high-grade serous ovarian cancer cell lines (COV362, CAOV3) to carboplatin, a standard of care for patients with ovarian cancer, and to the selective estrogen receptor modulator tamoxifen. FTY720 + tamoxifen was synergistic in vitro, and combinations of FTY720 + carboplatin or + tamoxifen were more effective than each single agent in a patient-derived xenograft model of ovarian carcinoma. FTY720 + tamoxifen arrested tumor growth. FTY720 + carboplatin induced tumor regressions, with tumor volumes reduced by ∼86% compared to initial tumor volumes. Anti-tumor efficacy was concomitant with increases in intracellular proapoptotic lipid ceramide. The data suggest that FTY720 + tamoxifen or carboplatin may be effective in treating ovarian tumors.

Exploring Metabolic Adaptations to the Acidic Microenvironment of Osteosarcoma Cells Unveils Sphingosine 1-Phosphate as a Valuable Therapeutic Target

“…FTY720 is FDA approved for the treatment of multiple sclerosis, and it is currently under trial for the treatment of breast carcinoma, glioblastoma and anaplastic astrocytoma (NCT03941743 and NCT02490930). FTY720 has several anticancer effects [ 77 , 78 , 79 , 80 , 81 ] but its activity in OS has not been explored so far. Despite being considered an S1P receptor modulator, FTY720 is also able to induce changes in the enzymes of the sphingolipid pathway, including SPHK1 [ 54 , 55 , 56 ], thus providing an explanation for the reduction of S1P seen in our model.…”

Induction of Lysosomal Membrane Permeabilization Is a Major Event of FTY720-Mediated Non-Apoptotic Cell Death in Human Glioma Cells

“…FTY720 is a synthetic compound produced by modification of a metabolite from I. sinclairii and has strong anti-cancer activity. For example, FTY720 induces cell death in multiple cancer cells [ 1 , 2 , 3 , 4 ] and sensitizes cancer cells to chemotherapy and radiotherapy [ 5 , 6 , 7 , 8 ]. Interestingly, FTY720 has also been seen to increase non-apoptotic cell death.…”

Does Fingolimod have anticancer effects? A meta-analysis and systematic review based on experimental animal models of various cancers

“…Literature screening and the summary of 31 studies Using "FTY720" or/and "animals" or/and "cancer" as the index, only 31 studies including 44 experiments of a total of 1485 research papers met our research criteria. The ow diagram for meta-analysis in detail was displayed in Fig. (Alshaker et al 2017;Azuma et al 2002;Chen et al 2014;Chua et al 2005;Estrada-Bernal et al 2012;Gstalder et al 2016;Hait et al 2015;Ho et al 2005;Katsuta et al 2017;Kreitzburg et al 2018;Lankadasari et al 2018; Lee et al 2004;Lee et al 2005;Leu et al 2016;Li et al 2013;Li et al 2018;Li et al 2017;Lifshitz et al 2017;Liu et al 2015;Liu et al 2014;Markovsky et al 2019;Martin et al 2017;Mousseau et al 2012;Muroyama et al 2017;Nagahashi et al 2016;Pchejetski et al 2010;Rosa et al 2013;Schmid et al 2007;Szymiczek et al 2017;Woo et al 2015;Xu et al 2015). Table S1 discussed study characteristics of 31 published articles from 1998 to 2019.…”