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Review
. 2015 Oct;19(10):2329-40.
doi: 10.1111/jcmm.12635. Epub 2015 Jul 14.

The Antineoplastic Properties of FTY720: Evidence for the Repurposing of Fingolimod

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Free PMC article
Review

The Antineoplastic Properties of FTY720: Evidence for the Repurposing of Fingolimod

Sathya Narayanan Patmanathan et al. J Cell Mol Med. .
Free PMC article

Abstract

Almost all drugs approved for use in humans possess potentially beneficial 'off-target' effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re-purposing FTY720 (also known as fingolimod, Gilenya(™)), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1-phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer-associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti-cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer-related cellular processes, and discuss its potential use as an anti-cancer drug.

Keywords: FTY720; S1P; apoptosis; cancer; cytotoxicity; fingolimod; sphingosine analogue.

Figures

Figure 1
Figure 1
Chemical structures of sphingosine-1-phosphate, myriocin, FTY720 and phosphorylated FTY720.
Figure 2
Figure 2
Repurposing of FTY720 for cancer therapy.
Figure 3
Figure 3
S1P signalling. S1P is generated by the sphingosine kinases, SPHK1 and SPHK2, and can be converted back to sphingosine by the S1P phosphatases, SGPP1 and SGPP2. Once secreted, S1P can act on one of at least five known S1P receptors (S1PR1-5). Activation of these receptors trigger downstream signalling, i.e. Rho, Rac, JNK (Jun N-terminal kinase), Akt (alpha serine/threonine-protein kinase), ERK (extracellular signal-regulated kinase), PLC (phospholipase C) and adenylate cyclase pathways, to regulate survival, apoptosis and motility of cells. FTY720 interferes with S1P signalling by binding to the S1PR1/3/4/5.
Figure 4
Figure 4
Effects of FTY720 on cancer cells.

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