Sphingosine-1-phosphate signaling: A novel target for simultaneous adjuvant treatment of triple negative breast cancer and chemotherapy-induced neuropathic pain.

Abstract

Triple-negative breast cancer (TNBC) is very aggressive with high metastatic and mortality rates and unfortunately, except for chemotherapy, there are few therapeutic options. The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) regulates numerous processes important for cancer progression, metastasis, and neuropathic pain. The pro-drug FTY720 (fingolimod, Gilenya) used to treat multiple sclerosis is phosphorylated in the body to a S1P mimic that binds to S1PRs, except S1PR2, and also acts as a functional antagonist of S1PR1. This review highlights current findings showing that FTY720 has multiple anti-cancer activities and simultaneously prevents formation and actions of S1P. Moreover, in mouse breast cancer models, treatment with FTY720 reduces tumor growth, metastasis, and enhances sensitivity of advanced and hormonal refractory breast cancer and TNBC to conventional therapies. We discuss recent studies demonstrating that neuropathic pain induced by the chemotherapeutic bortezomib is also greatly reduced by administration of clinically relevant doses of FTY720, likely by targeting S1PR1 on astrocytes. FTY720 also shows promising anticancer potential in pre-clinical studies and is FDA approved, thus we suggest in this review that further studies are needed to pave the way for fast-tracking approval of FTY720/fingolimod for enhancing chemotherapy effectiveness and reduction of painful neuropathies.