Institute of Toxicology, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany.
Institute of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
Pharmacol Res. 2015 Jan;91:47-56. doi: 10.1016/j.phrs.2014.11.003. Epub 2014 Nov 21.
The anticancer efficacy of anthracyclines is limited by cumulative dose-dependent early and delayed cardiotoxicity resulting in congestive heart failure. Mechanisms responsible for anthracycline-induced heart damage are controversially discussed and effective preventive measures are preferable. Here, we analyzed the influence of the lipid lowering drug lovastatin on anthracycline-induced late cardiotoxicity three month after treatment of C57BL/6 mice with five low doses of doxorubicin (5×3mg/kg BW; i.p.). Doxorubicin increased the cardiac mRNA levels of BNP, IL-6 and CTGF, while the expression of ANP remained unchanged. Lovastatin counteracted these persisting cardiac stress responses evoked by the anthracycline. Doxorubicin-induced fibrotic alterations were neither detected by histochemical collagen staining of heart sections nor by analysis of the mRNA expression of collagens. Extensive qRT-PCR-array based analyses revealed a large increase in the mRNA level of heat shock protein Hspa1b in doxorubicin-treated mice, which was mitigated by lovastatin co-treatment. Electron microscopy together with qPCR-based analysis of mitochondrial DNA content indicate that lovastatin attenuates doxorubicin-stimulated hyperproliferation of mitochondria. This was not paralleled by increased expression of oxidative stress responsive genes or senescence-associated proteins. Echocardiographic analyses disclosed that lovastatin protects from the doxorubicin-induced decrease in the left ventricular posterior wall diameter (LVPWD), while constrictions in fractional shortening (FS) and ejection fraction (EF) evoked by doxorubicin were not amended by the statin. Taken together, the data suggest beneficial effects of lovastatin against doxorubicin-induced delayed cardiotoxicity. Clinical studies are preferable to scrutinize the usefulness of statins for the prevention of anthracycline-induced late cardiotoxicity.
蒽环类药物的抗癌疗效受到累积剂量依赖性早期和延迟性心脏毒性的限制，导致充血性心力衰竭。蒽环类药物诱导心脏损伤的机制存在争议，因此更倾向于采取有效的预防措施。在这里，我们分析了降脂药物洛伐他汀对 C57BL/6 小鼠腹腔注射五低剂量阿霉素（5×3mg/kg BW）治疗 3 个月后晚期心脏毒性的影响。阿霉素增加了 BNP、IL-6 和 CTGF 的心脏 mRNA 水平，而 ANP 的表达保持不变。洛伐他汀对抗了蒽环类药物引起的持续的心脏应激反应。洛伐他汀还减弱了阿霉素引起的纤维化改变，通过心脏切片胶原组织化学染色或胶原 mRNA 表达分析均未检测到。广泛的 qRT-PCR 阵列分析显示，阿霉素处理的小鼠中热休克蛋白 Hspa1b 的 mRNA 水平显著增加，而洛伐他汀共同处理减轻了这种增加。电子显微镜和基于 qPCR 的线粒体 DNA 含量分析表明，洛伐他汀减弱了阿霉素刺激的线粒体过度增殖。这与氧化应激反应基因或衰老相关蛋白的表达增加无关。超声心动图分析显示，洛伐他汀可防止阿霉素引起的左心室后壁直径（LVPWD）减小，而阿霉素引起的短轴缩短率（FS）和射血分数（EF）的收缩未被他汀类药物改善。总之，这些数据表明洛伐他汀对阿霉素引起的迟发性心脏毒性具有有益作用。临床研究更有利于探讨他汀类药物预防蒽环类药物引起的迟发性心脏毒性的作用。
