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. 2016 Apr 26;7(17):23106-27.
doi: 10.18632/oncotarget.7145.

The Emerging Role of FTY720 (Fingolimod) in Cancer Treatment

Free PMC article

The Emerging Role of FTY720 (Fingolimod) in Cancer Treatment

Christopher White et al. Oncotarget. .
Free PMC article


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.

Keywords: FTY720; cancer; fingolimod; sphingolipid; sphingosine kinase.

Conflict of interest statement

CONFLICT OF INTERESTS The authors have no financial, commercial or other relationships of a declarable nature relevant to the materials discussed in the manuscript.


Figure 1
Figure 1. Sphingolipid rheostat
Ceramide and sphingosine are intracellular lipid second messengers, which induce activation of apoptotic pathways. In turn, SK1 can phosphorylate sphingosine to yield S1P, a lipid second messenger that activates anti-apoptotic pathways and antagonises the effects of ceramide and sphingosine. The intracellular balance between ceramide, sphingosine and S1P determines the cell fate. PKC - protein kinase C; MAPK - mitogen-activated protein kinases; JNK - c-Jun N-terminal kinases; SAPK - stress activated protein kinase; NFkB - nuclear factor kappa B; PLC - phospholipase C; Bcl2 - B cell lymphoma 2, AP-1 - activator protein 1 (reviewed in [248] and [249]).
Figure 2
Figure 2
SK1/S1P signalling pathway. Tumour necrosis factor alfa, growth factors and cytokines activate receptor tyrosine kinases, G-protein coupled receptors, toll like receptors, which induce phosphorylation of sphingosine kinase 1 (SK1, often through ERK1/2 and PKC), its translocation to plasma membrane and generation of sphingosine-1-phosphate (S1P) from sphingosine (reviewed in [250]). S1P can then be exported outside of the cell where it acts in a paracrine or autocrine manner and activates 5 specific S1P receptors (S1P1-5). Upon coupling with S1P, these receptors can activate downstream signalling pathways leading to cell proliferation, migration and gene expression. PKC - protein kinase C; (reviewed in [248] and [249]).
Figure 3
Figure 3. Structures of sphingosine (A) and FTY720 (B)
Figure 4
Figure 4. Molecular targets of FTY720
FTY720 inhibits SK1 and blocks the activation of multiple targets of this enzyme. In addition it can directly or indirectly inhibit multiple intracellular targets responsible for cell proliferation, migration and angiogenesis. It further activates mitochondrial permeability transition pore (MPTP), cytochrome c and effector caspases. P-gp - P-glycoprotein, MRP1 - multidrug resistance protein, ROBO1 - roundabout homolog 1, ROCK1 - rho-associated, coiled-coil-containing protein kinase 1, Stat5 - signal transducer and activator of transcription 5, FAK – focal adhesion kinase, MMP – matrix metalloprotease, TIMP – tissue inhibitor of metallopeptidase, CDK - cyclin-dependent kinase.

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