Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA.
Biochem Biophys Res Commun. 2011 Jan 7;404(1):321-3. doi: 10.1016/j.bbrc.2010.11.115. Epub 2010 Dec 3.
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 24 h with FTY720 (up to 10 μM) inhibited ASMase by >80% and this could be reversed by pre-treatment with the cathepsin protease inhibitor leupeptin (5 μM). 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.
免疫调节剂药物芬戈莫德（FTY720），作为首个用于治疗多发性硬化症（MS）的口服鞘氨醇-1-磷酸受体（S1P-R）调节剂上市，也抑制溶酶体酸性鞘磷脂酶（ASMase）。用 FTY720（高达 10 μM）处理培养细胞 24 小时，可使 ASMase 抑制超过 80%，而用半胱氨酸蛋白酶抑制剂亮抑酶肽（5 μM）预处理可逆转这种抑制。相比之下，中性鞘磷脂酶活性不受影响，鞘氨醇-1-磷酸处理对 ASMase 没有影响。RT-PCR 显示 ASMase mRNA 没有被抑制，FTY720 或 FTY720-磷酸对 ASMase 没有直接的（体外）抑制作用。这表明其抑制机制与三环类抗抑郁药（如去甲丙咪嗪）相似，后者也是亲脂性阳离子药物。去甲丙咪嗪和 FTY720 处理均降低了 ASMase，而对其他溶酶体水解酶没有明显抑制，但大多数水解酶的分泌增加（高达 50%的增加），这为这些药物引起溶酶体破裂提供了更多证据。
