Suppressive effects of statins on acute promyelocytic leukemia cells
Suppressive effects of statins on acute promyelocytic leukemia cells
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DOI：
10.1158/0008-5472.can-06-3686
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发表时间：
2007-05-01
期刊：
影响因子：
11.2
通讯作者：
Platanias, Leonidas C.
中科院分区：
文献类型：
--
作者：
Sassano, Antonella;Katsoulidis, Efstratios;Platanias, Leonidas C.
他汀类药物家族包括3-羟基-3-甲基戊二酰-CoA还原酶的药理学抑制剂，其是胆固醇生物合成的有效调节剂。他汀类药物除具有降胆固醇作用外，还能抑制细胞增殖，促进体外恶性肿瘤细胞凋亡，但其在恶性肿瘤治疗中的潜在治疗作用仍有待确定。我们研究了他汀类药物对急性髓性白血病（AML）细胞生长和分化的影响。阿托伐他汀和氟伐他汀被发现是NB 4急性早幼粒细胞白血病（APL）细胞系的细胞分化和凋亡的有效诱导剂。这种效应与小G蛋白Racl/Cdc 42的激活和c-jun NH 2-末端激酶激酶途径的下游参与相关，其功能被认为是产生促凋亡反应所必需的。重要的是，不同的他汀类药物被发现，以提高全反式维甲酸（ATRA）依赖的分化APL原始细胞和逆转耐药的抗白血病作用的ATRA。此外，氟伐他汀表现出对AML患者的原代骨髓来源的白血病祖细胞的生长抑制特性，并增强了ATRA对白血病祖细胞集落形成的抑制作用。总之，这些研究表明，他汀类药物在体外表现出有效的抗白血病特性，并提高了他汀类药物与ATRA的组合可能是克服白血病细胞对ATRA耐药性发展的有效方法的可能性。
The family of statins includes pharmacologic inhibitors of the 3-hydroxy-3-methylglutaryi-CoA reductase that are potent regulators of cholesterol biosynthesis. In addition to their cholesterol-lowering effects, statins inhibit cell proliferation and promote apoptosis of malignant cells in vitro, but their potential therapeutic roles in the treatment of malignancies remain to be defined. We examined the effects of statins on the growth and differentiation of acute myeloid leukemia (AML) cells. Atorvastatin and fluvastatin were found to be potent inducers of cell differentiation and apoptosis of the NB4 acute promyelocytic leukemia (APL) cell line. Such effects correlated with activation of the small G-proteins Racl/Cdc42 and downstream engagement of the c-jun NH2-terminal kinase kinase pathway, whose function was found to be essential for the generation of proapoptotic responses. Importantly, different statins were found to enhance all-trans-retinoic acid (ATRA)-dependent differentiation of APL blasts and reverse resistance to the antileukemic effects of ATRA. In addition, fluvastatin exhibited growth-inhibitory properties on primary bone marrow-derived leukemic progenitors from patients with AML and enhanced the suppressive effects of ATRA on leukemic progenitor colony formation. Altogether, these studies establish that statins exhibit potent antileukemic properties in vitro and raise the possibility that combinations of statins with ATRA may be an effective approach to overcome the development of ATRA resistance by the leukemic cells.