Sassano Antonella, Katsoulidis Efstratios, Antico Giovanni, Altman Jessica K, Redig Amanda J, Minucci Saverio, Tallman Martin S, Platanias Leonidas C
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology/Oncology, Northwestern University Medical School and Lakeside VA Medical Center, Chicago, Illinois 60611, USA.
Cancer Res. 2007 May 1;67(9):4524-32. doi: 10.1158/0008-5472.CAN-06-3686.
The family of statins includes pharmacologic inhibitors of the 3-hydroxy-3-methylglutaryl-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 Rac1/Cdc42 and downstream engagement of the c-Jun NH(2)-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.
他汀类药物家族包括3-羟基-3-甲基戊二酰辅酶A还原酶的药理学抑制剂，它们是胆固醇生物合成的有效调节剂。除了降低胆固醇的作用外，他汀类药物在体外可抑制癌细胞增殖并促进其凋亡，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系白血病（AML）细胞生长和分化的影响。发现阿托伐他汀和氟伐他汀是NB4急性早幼粒细胞白血病（APL）细胞系细胞分化和凋亡的有效诱导剂。这些作用与小G蛋白Rac1/Cdc42的激活以及c-Jun氨基末端激酶激酶途径的下游参与相关，发现该途径的功能对于促凋亡反应的产生至关重要。重要的是，发现不同的他汀类药物可增强APL原始细胞的全反式维甲酸（ATRA）依赖性分化，并逆转对ATRA抗白血病作用的耐药性。此外，氟伐他汀对AML患者的原代骨髓来源白血病祖细胞具有生长抑制特性，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具有强大的抗白血病特性，并增加了他汀类药物与ATRA联合使用可能是克服白血病细胞产生ATRA耐药性的有效方法的可能性。
