Abstract
FTY720 (Fingolimod) is a clinically approved immunomodulating therapy for multiple sclerosis that sequesters T-cells to lymph nodes through functional antagonism of sphingosine-1-phosphate 1 receptor. FTY720 also demonstrates a proven efficacy in multiple in vitro and in vivo cancer models, suggesting a potential therapeutic role in cancer patients. A potential anticancer mechanism of FTY720 is through the inhibition of sphingosine kinase 1, a proto-oncogene with in vitro and clinical cancer association. In addition, FTY720's anticancer properties may be attributable to actions on several other molecular targets. This study focuses on reviewing the emerging evidence regarding the anticancer properties and molecular targets of FTY720. While the clinical transition of FTY720 is currently limited by its immune suppression effects, studies aiming at FTY720 delivery and release together with identifying its key synergetic combinations and relevant patient subsets may lead to its rapid introduction into the clinic.
Highlights
Introduction to sphingolipid metabolismSphingolipids are one of the major components of eukaryotic cell plasma membranes
Cleavage of a pro-apoptotic sphingolipid ceramide yields pro-apoptotic sphingosine that is phosphorylated by sphingosine kinases (SKs) to anti-apoptotic sphingosine-1phosphate (S1P) (Figure 1)
SK1 inhibition by FTY720 was shown to lead to prostate cancer cells apoptosis [88] and reduction of the expression of the androgen receptor [134]
Summary
Introduction to sphingolipid metabolismSphingolipids are one of the major components of eukaryotic cell plasma membranes. Treatment of colorectal cancer cells with FTY720 shows an additive effect with 5-fluorouracil, SN-38, and oxaliplatin [176], and results in resensitization to cetuximab both in vitro and in vivo with inhibition of tumour growth, interference with signal transduction, induction of cancer cells apoptosis and prolongation of mice survival [177]. In cisplatin-resistant SK-Mel-28 melanoma cells FTY720 induces SK1 degradation by p53-independent caspase activation and may inhibit the PI3K/Akt/mTOR pathway, related to chemoresistance mainly through escape from apoptosis [188].
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