Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Germany.
Cell Death Dis. 2011 Aug 11;2(8):e190. doi: 10.1038/cddis.2011.65.
Normal tissue damage limits the efficacy of anticancer therapy. For anthracyclines, the clinically most relevant adverse effect is cardiotoxicity. The mechanisms involved are poorly understood and putative cardioprotectants are controversially discussed. Here, we show that the lipid-lowering drug lovastatin protects rat H9c2 cardiomyoblasts from doxorubicin in vitro. Protection by lovastatin is related to inhibition of the Ras-homologous GTPase Rac1. It rests on a reduced formation of DNA double-strand breaks, resulting from the inhibition of topoisomerase II by doxorubicin. Doxorubicin transport and reactive oxygen species are not involved. Protection by lovastatin was confirmed in vivo. In mice, lovastatin mitigated acute doxorubicin-induced heart and liver damage as indicated by reduced mRNA levels of the pro-fibrotic cytokine connective tissue growth factor (CTGF) and pro-inflammatory cytokines, respectively. Lovastatin also protected from doxorubicin-provoked subacute cardiac damage as shown by lowered mRNA levels of CTGF and atrial natriuretic peptide. Increase in the serum concentration of troponin I and cardiac fibrosis following doxorubicin treatment were also reduced by lovastatin. Whereas protecting the heart from harmful doxorubicin effects, lovastatin augmented its anticancer efficacy in a mouse xenograft model with human sarcoma cells. These data show that statins lower the incidence of cardiac tissue injury after anthracycline treatment in a Rac1-dependent manner, without impairing the therapeutic efficacy.
正常组织损伤限制了抗癌治疗的疗效。对于蒽环类药物，临床上最相关的不良反应是心脏毒性。其涉及的机制尚未完全了解，潜在的心脏保护剂也存在争议。在这里，我们表明降脂药洛伐他汀可在体外保护大鼠 H9c2 心肌细胞免受阿霉素的损害。洛伐他汀的保护作用与 Ras 同源 GTP 酶 Rac1 的抑制有关。它依赖于阿霉素抑制拓扑异构酶 II 导致的 DNA 双链断裂形成减少。阿霉素的转运和活性氧均不参与其中。洛伐他汀在体内的保护作用也得到了证实。在小鼠中，洛伐他汀减轻了急性阿霉素诱导的心脏和肝脏损伤，这表现在促纤维化细胞因子结缔组织生长因子 (CTGF) 和促炎细胞因子的 mRNA 水平降低。洛伐他汀还可预防阿霉素引起的亚急性心脏损伤，表现为 CTGF 和心钠肽的 mRNA 水平降低。阿霉素治疗后血清肌钙蛋白 I 浓度升高和心脏纤维化也被洛伐他汀减少。洛伐他汀在保护心脏免受有害阿霉素作用的同时，在人肉瘤细胞的小鼠异种移植模型中增强了其抗癌疗效。这些数据表明，他汀类药物以 Rac1 依赖的方式降低了蒽环类药物治疗后的心脏组织损伤发生率，而不损害治疗效果。
