INSERM UMR1037-Cancer Research Center of Toulouse, BP84225, 31432 Toulouse Cedex 4, France.
Recent Pat Anticancer Drug Discov. 2011 Sep;6(3):324-33. doi: 10.2174/157489211796957801.
Resistance to death receptor ligands (such as FasL and TRAIL) and anticancer treatments is a hallmark of cancer cells. Ceramide, a biologically active sphingolipid, antagonizes cell growth and promotes apoptosis and non-apoptotic forms of cell death. The intracellular levels of ceramide are highly regulated via complex metabolic pathways. Sphingomyelin synthases (SMS) 1 and 2 convert ceramide to sphingomyelin (SM), a ubiquitous phospholipid in mammals. A growing body of evidence in the literature indicates that SMSs likely modulate hematological cell growth and sensitivity to stress-induced apoptosis. On one hand, complete and sustained inhibition of SMS activity is likely to alter membrane composition and properties through membrane SM depletion, perturbing intracellular signaling pathways and leukemia cell growth and conferring partial resistance to death receptor ligands. On the other hand, different patents & reports point to anti-apoptotic functions for SMSs. In patients with chemoresistant leukemia, a decreased intracellular ceramide level was associated with a higher SMS activity. Thus, SMSs and cofactors may constitute original pharmacological targets to treat leukemia.
细胞对死亡受体配体（如 FasL 和 TRAIL）和抗癌治疗的抵抗是癌细胞的一个标志。神经酰胺是一种具有生物活性的神经鞘脂，能拮抗细胞生长，促进细胞凋亡和非凋亡性细胞死亡。神经酰胺的细胞内水平通过复杂的代谢途径得到高度调节。鞘氨醇合酶（SMS）1 和 2 将神经酰胺转化为鞘磷脂（SM），SM 是哺乳动物中普遍存在的磷脂。越来越多的文献证据表明，SMS 可能调节血液细胞的生长和对应激诱导凋亡的敏感性。一方面，SMS 活性的完全和持续抑制可能通过膜 SM 耗竭改变膜组成和性质，扰乱细胞内信号通路和白血病细胞的生长，并对死亡受体配体产生部分抵抗。另一方面，不同的专利和报告指出 SMS 具有抗凋亡功能。在化疗耐药性白血病患者中，细胞内神经酰胺水平降低与 SMS 活性升高有关。因此，SMS 和辅助因子可能构成治疗白血病的原始药理学靶点。
