Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity
Arsenic trioxide induces accumulation of cytotoxic levels of ceramide in acute promyelocytic leukemia and adult T-cell leukemia/lymphoma cells through de novo ceramide synthesis and inhibition of glucosylceramide synthase activity
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DOI：
10.3324/haematol.10968
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发表时间：
2007-06-01
期刊：
影响因子：
10.1
通讯作者：
Bazarbachi, Ali
中科院分区：
文献类型：
--
作者：
Dbaibo, Ghassan S.;Kfoury, Youmna;Bazarbachi, Ali
背景和目的三氧化二砷 (ATO) 是治疗急性早幼粒细胞白血病 (APL) 的有效方法，并有可能治疗 I 型人类 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)。许多细胞毒性药物通过鞘脂分解产物神经酰胺的产生和积累来诱导细胞凋亡，神经酰胺是细胞对应激反应的协调剂。因此，我们研究了神经酰胺对 APL 和 ATL 中 ATO 作用机制的贡献。 设计和方法 培养人类 APL 衍生细胞系 (NB4)、各种 ATL 衍生细胞系和 HTLV-I 阴性恶性 T 细胞系，并用 ATO 处理。进行生长和凋亡测定。测量了神经酰胺、二酰甘油、鞘磷脂活性、鞘磷脂质量、葡萄糖神经酰胺合酶活性和从头神经酰胺合成。结果用临床可达到的浓度的 ATO 处理 APL 和 ATL 衍生细胞，诱导神经酰胺细胞毒性水平的积累。 ATO 对 APL 细胞中神经酰胺水平的影响比全反式视黄酸 (ATRA) 更有效。 ATO 下调中性鞘磷脂酶活性。与 ATRA 的作用相反，ATO 诱导的神经酰胺积累并不是由于酸性鞘磷脂酶的诱导，而是由于神经酰胺从头合成和葡萄糖神经酰胺合酶活性的抑制所致。有趣的是，尽管 ATL 细胞中的途径有缺陷，但 ATO 对 APL 和 ATL 衍生细胞中神经酰胺从头合成的影响相似。 解释和结论这些结果表明，ATO 诱导的神经酰胺积累可能代表 ATO 作用的一般介质，这为针对这一重要鞘脂第二信使代谢途径的新治疗干预措施铺平了道路。
Background and ObjectivesArsenic 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.Design and MethodsA 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, sphingomyelinese activity, sphingomyelin mass, glucosylceramide synthase activity and the de novo ceramide synthesis.ResultsTreatment 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.Interpretation and ConclusionsThese 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.