文章：

他汀类药物和癌症预防

Statins and cancer prevention

原文发布日期：2005-12-01

DOI: 10.1038/nrc1751

类型: Review Article

开放获取: 否

要点：

1. Statins function in the mevalonate pathway as small-molecule inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which lowers cholesterol. These agents are effective in preventing cardiovascular disease (CVD), largely because of this effect.
2. Large randomized controlled trials (RCTs) that analysed the effects of statins and other lipid-lowering agents (for example, fibrates, nicotinic acid and cholestyramine) to prevent CVD included safety monitoring to address whether statins increased cancer incidence and cancer mortality. Ironically, these results were the first to suggest that statins can prevent cancer.
3. In addition to the HMG-CoA-dependent effects, statins have important cholesterol/HMG-CoA-independent effects, such as effects on lymphocyte-function-associated antigen 1 (LFA1), that are thought to contribute to potential cancer prevention.
4. Important work in preclinical models of colorectal and breast cancer, and melanoma, indicates that statin anticancer effects involve the inhibition of geranylgeranylation, primarily of Rho proteins.
5. Secondary results of the CVD RCTs, as well as observational and preclinical studies, indicate that statins have a strong potential for preventing colorectal cancer and melanoma.
6. The beneficial effects of statins on inhibiting carcinogenesis could involve their effects on important disease pathways including inflammation, immunomodulation and angiogenesis.
7. Statins are broad-spectrum agents. Current research is revealing important new statin targets (such as LFA1, Rho isoforms, and post-prenylation enzymes) leading to the development of more-specifically targeted agents for cancer prevention.

要点翻译：

1. 他汀类药物在甲羟戊酸途径中作为3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的小分子抑制剂，从而降低胆固醇水平。这类药物能有效预防心血管疾病，主要归功于此作用机制。
2. 大型随机对照试验在分析他汀类及其他降脂药物（如贝特类、烟酸和考来烯胺）预防心血管疾病效果时，通过安全性监测评估了他汀类药物是否会增加癌症发病率和死亡率。具有讽刺意味的是，这些结果首次提示他汀类药物可能具有防癌作用。
3. 除HMG-CoA依赖性作用外，他汀类药物还具有重要的胆固醇/HMG-CoA非依赖性效应（如对淋巴细胞功能相关抗原1的作用），这些效应被认为有助于其潜在的癌症预防作用。
4. 在结直肠癌、乳腺癌和黑色素瘤的临床前模型中的重要研究表明，他汀类药物的抗癌作用涉及对蛋白质香叶基香叶基化（主要是Rho蛋白）的抑制。
5. 心血管疾病随机对照试验的次要结果以及观察性和临床前研究均表明，他汀类药物在预防结直肠癌和黑色素瘤方面具有巨大潜力。
6. 他汀类药物抑制致癌作用的有益效应可能通过影响关键疾病通路实现，包括炎症、免疫调节和血管生成等途径。
7. 他汀类药物属于广谱制剂。当前研究正揭示其重要新靶点（如LFA1、Rho亚型及翻译后异戊烯化酶），这将推动开发更具靶向性的癌症预防药物。

英文摘要：

Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.

摘要翻译： 

随机对照试验表明，他汀类药物在预防心血管疾病的同时，意外地显示出降低结直肠癌和黑色素瘤风险的益处。这些发现促使人们深入研究他汀类药物在癌症预防中的作用，包括近期多项基于大规模人群的研究显示，他汀类药物与总体癌症、结直肠癌和前列腺癌的风险降低相关。理解他汀类药物复杂的细胞效应（例如对血管生成和炎症的影响）及其潜在的分子机制（例如依赖3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的过程，涉及Rho蛋白的香叶基香叶基化；以及不依赖HMG-CoA的过程，涉及淋巴细胞功能相关抗原1），将有助于开发用于癌症预防的分子靶向药物。这一理解也可能有助于开发用于治疗其他与衰老相关疾病的药物，这些疾病具有相互关联的分子通路。

原文链接：

Statins and cancer prevention