Gilenya (FTY720) inhibits acid sphingomyelinase by a mechanism similar to tricyclic antidepressants

Abstract

The immunomodulator drug Gilenya (FTY720), marketed as the first oral sphingosine 1-phosphate receptor (S1P-R) modulator for treatment of Multiple Sclerosis (MS) also inhibits lysosomal acid sphingomyelinase (ASMase). Treatment of cultured cells for 24h with FTY720 (up to 10μM) inhibited ASMase by >80% and this could be reversed by pre-treatment with the cathepsin protease inhibitor leupeptin (5μM). In contrast, neutral sphingomyelinase activity was unaffected and sphingosine-1-phosphate treatment had no effect on ASMase. RT-PCR revealed no inhibition of ASMase mRNA and there was no direct (in vitro) inhibition of ASMase by either FTY720 or FTY720-phosphate. This suggests that its mechanism of inhibition is similar to that of tricyclic anti-depressants such as desipramine, which are also amphiphilic cationic drugs. Both Desipramine and FTY720 treatment reduced ASMase without significant inhibition of other lysosomal hydrolases but most hydrolases showed increased secretion (up to a 50% increase) providing more evidence of lysosomal disruption by these drugs.

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

“…Other compounds have also been described to induce loss of functional aSMase, such as the calmodulin antagonist W-7 (Masson et al, 1989), SR33557 (Jaffrezou et al, 1991), cocaine (Nassogne et al, 2004), the S1P receptor antagonist FTY720 (Dawson and Qin, 2011) and other cationic amphiphilic drugs (CAD) (Yoshida et al, 1985). Since none of them inhibit aSMase in vitro, it has been suggested they have alternative mechanism of action, similar to the ones described below.…”

Inhibition of P2X7 receptors improves outcomes after traumatic brain injury in rats

“…The therapeutic action of FTY720 in MS is to inhibit the exit of autoreactive memory T cells from secondary lymphoid organs to produce a peripheral lymphopenia [54]. FTY720 has been marketed as the first oral sphingosine-1-phosphate receptor modulator for the treatment of MS, but it also inhibits lysosomal A-SMase [16].…”

“…As such, P2X7R antagonists and inhibitors of p38 MAPK and A-SMase can regulate MV shedding and IL-1β release from glial cells. FTY720 (Gilenya), an immunomodulator drug marketed as the first oral sphingosine-1-phosphate receptor modulator for treatment of multiple sclerosis, also inhibits lysosomal A-SMase [16].…”

Evolving concepts in cancer therapy through targeting sphingolipid metabolism

“…Since desipramine-treatment can induce apoptosis in various cell lines possibly through endoplasmic stress, induction of apoptosis via FTY720-treatment may use a similar, non-S1PR/SK-specific pathway [246, 247]…”