Potential antitumor effects of statins (Review).
Potential antitumor effects of statins (Review).
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他汀类药物的潜在抗肿瘤作用（综述）。
DOI：
10.3892/ijo.23.4.1055
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发表时间：
2003
影响因子：
5.2
通讯作者：
J. Gołąb
中科院分区：
文献类型：
--
作者：
M. Jakóbisiak;J. Gołąb
他汀类药物已被引入临床用于治疗高胆固醇血症，是 3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶的竞争性抑制剂，3-羟基-3-甲基戊二酰辅酶 A (HMG-CoA) 还原酶是控制 HMG-CoA 转化为甲羟戊酸 (MA) 的主要限速酶。 MA 是类异戊二烯化合物（包括胆固醇、多醇和泛醌）生物合成的前体。此外，甲羟戊酸衍生的异戊二烯基团能够实现许多蛋白质（例如 Ras 和 Rho 蛋白）的精确细胞定位和功能。因此，除了降低胆固醇水平外，他汀类药物对许多重要的细胞功能（包括细胞增殖、分化和存活）发挥多效作用，而且还参与细胞形状和运动的调节。他汀类药物已被证明可以抑制多种肿瘤细胞的增殖并诱导细胞凋亡。还发现它们在动物肿瘤模型中表现出针对黑色素瘤、乳腺癌、胰腺癌、纤维肉瘤、神经胶质瘤、神经母细胞瘤和淋巴瘤的抗肿瘤作用，从而延缓肿瘤生长和/或抑制转移过程。在临床前研究中，他汀类药物也被证明可以增强某些细胞因子和化疗药物的抗肿瘤作用。他汀类药物抗肿瘤活性的分子机制尚未完全阐明，但干扰 Ras 和 Rho 家族 GTPases 的功能、抑制某些细胞周期蛋白依赖性激酶 (CDK) 的活性以及激活 CDK 抑制剂似乎都参与了这种活性。他汀类药物在癌症患者中的多项临床研究结果，包括 I 期、I/II 期和 II 期试验的结果已经发表。虽然评估疗效并不是早期临床试验的目的，现阶段所有结论可能还为时过早，但已经得出了一些初步结论。这些研究的结果没有显示他汀类药物对癌症患者有任何显着的治疗作用。然而，其中一项研究的结果表明他汀类药物可以有效增强某些化疗药物的治疗活性。这一观察结果似乎与临床前研究的结果一致。然而，由于他汀类药物的毒副作用在与其他一些药物联合使用时特别明显，因此在计划基于包括他汀类药物在内的癌症患者联合治疗的临床试验时应非常谨慎。
Statins, which have been introduced to the clinic for the treatment of hypercholesterolemia, are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the major rate-limiting enzyme that controls the conversion of HMG-CoA to mevalonic acid (MA). MA is the precursor in the biosynthesis of isoprenoid compounds including cholesterol, dolichol and ubiquinone. Furthermore, mevalonate-derived prenyl groups enable precise cellular localization and function of many proteins such as Ras and Rho proteins. Therefore, besides lowering cholesterol level, statins exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival but also participate in the regulation of cell shape and motility. Statins have been shown to inhibit proliferation and to induce apoptosis in a variety of tumor cells. They have also been found to display antitumor effects against melanoma, mammary carcinoma, pancreatic adenocarcinoma, fibrosarcoma, glioma, neuroblastoma, and lymphoma in animal tumor models resulting in retardation of tumor growth, and/or inhibition of the metastatic process. In preclinical studies statins have also been demonstrated to potentiate the antitumor effects of some cytokines and chemotherapeutics. The molecular mechanisms underlying antitumor activity of statins have not been fully elucidated but interference with the function of Ras and Rho family GTPases, inhibition of the activity of certain cyclin-dependent kinases (CDK), and activation of CDK inhibitors, all seem to participate in this activity. The results of several clinical studies of statins in cancer patients including phase I, phase I/II, and phase II trials have been published. Although evaluation of the therapeutic efficacy is not the purpose of early clinical trials and all conclusions might be premature at this stage, some preliminary conclusions have already been drawn. The results of these studies do not show any significant therapeutic effects of statins in cancer patients. However, the results of one of these studies suggest that statins could effectively strengthen the therapeutic activity of some chemotherapeutics. This observation seems to agree with the results of preclinical studies. However, as toxic side effects of statins have been particularly evident in their combination with some other drugs great caution should be advised while planning clinical trials based on combination therapy including statins in cancer patients.