Dbaibo Ghassan S, Kfoury Youmna, Darwiche Nadine, Panjarian Shoghag, Kozhaya Lina, Nasr Rihab, Abdallah Mazen, Hermine Olivier, El-Sabban Marwan, de Thé Hugues, Bazarbachi Ali
Department of Pediatrics, American University of Beirut, Beirut, Lebanon.
Haematologica. 2007 Jun;92(6):753-62. doi: 10.3324/haematol.10968.
Arsenic trioxide (ATO) is an effective treatment for acute promyelocytic leukemia (APL) and potentially for human T-cell leukemia virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATL). Many cytotoxic drugs induce apoptosis through the generation and accumulation of the sphingolipid breakdown product, ceramide, a coordinator of the cellular response to stress. We, therefore, investigated the contribution of ceramide to the mechanism of action of ATO in APL and ATL.
A human APL-derived cell line (NB4), various ATL-derived lines and an HTLV-I-negative malignant T-cell line were cultured and treated with ATO. Growth and apoptosis assays were conducted. Measurements were made of ceramide, diacylglycerol, sphingomyelinase activity, sphingomyelin mass, glucosylceramide synthase activity and the de novo ceramide synthesis.
Treatment of APL and ATL-derived cells with a clinically achievable concentration of ATO induced accumulation of cytotoxic levels of ceramide. The effects of ATO on ceramide levels in APL cells were more potent than those of all-trans retinoic acid (ATRA). ATO downregulated neutral sphingomyelinase activity. In contrast to the effect of ATRA, ATO-induced ceramide accumulation was not due to induction of acidic sphingomyelinase, but rather resulted from both de novo ceramide synthesis and inhibition of glucosylceramide synthase activity. Interestingly, the effects of ATO on de novo ceramide synthesis were similar in APL and ATL-derived cells despite the defective pathway in ATL cells.
These results indicate that ATO-induced ceramide accumulation may represent a general mediator of the effects of ATO, which paves the way for new therapeutic interventions that target the metabolic pathway of this important sphingolipid secondary messenger.
三氧化二砷（ATO）是治疗急性早幼粒细胞白血病（APL）的有效药物，对人I型嗜T细胞白血病病毒（HTLV-I）相关的成人T细胞白血病/淋巴瘤（ATL）也可能有效。许多细胞毒性药物通过鞘脂分解产物神经酰胺的生成和积累诱导细胞凋亡，神经酰胺是细胞应激反应的协调者。因此，我们研究了神经酰胺在ATO治疗APL和ATL作用机制中的作用。
培养人APL来源的细胞系（NB4）、多种ATL来源的细胞系以及HTLV-I阴性恶性T细胞系，并用ATO处理。进行生长和凋亡检测。测定神经酰胺、二酰基甘油、鞘磷脂酶活性、鞘磷脂含量、葡萄糖神经酰胺合成酶活性以及神经酰胺的从头合成。
用临床可达到的ATO浓度处理APL和ATL来源的细胞，可诱导细胞毒性水平的神经酰胺积累。ATO对APL细胞中神经酰胺水平的影响比全反式维甲酸（ATRA）更强。ATO下调中性鞘磷脂酶活性。与ATRA的作用不同，ATO诱导的神经酰胺积累不是由于酸性鞘磷脂酶的诱导，而是由于神经酰胺的从头合成和葡萄糖神经酰胺合成酶活性的抑制。有趣的是，尽管ATL细胞中的途径存在缺陷，但ATO对APL和ATL来源细胞中神经酰胺从头合成的影响相似。
这些结果表明，ATO诱导的神经酰胺积累可能是ATO作用的一般介质，这为针对这种重要鞘脂二级信使代谢途径的新治疗干预铺平了道路。
