Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto-USP, Avenida do Café s/n, Ribeirão Preto, SP, Brazil.
Chem Biol Interact. 2011 Jan 15;189(1-2):45-51. doi: 10.1016/j.cbi.2010.10.014. Epub 2010 Oct 31.
Cisplatin is a highly effective chemotherapeutic agent which causes severe nephrotoxicity. Studies have suggested that reactive oxygen species, mainly generated in mitochondria, play a central role in cisplatin-induced renal damage. A wide range of antioxidants have been evaluated as possible protective agents against cisplatin-induced nephrotoxicity; however a safe and efficacious compound has not yet been found. The present study is the first to evaluate the protective potential of carvedilol, a beta-blocker with strong antioxidant properties, against the mitochondrial oxidative stress and apoptosis in kidney of rats treated with cisplatin. The following cisplatin-induced toxic effects were prevented by carvedilol: increased plasmatic levels of creatinine and blood urea nitrogen (BUN); lipid peroxidation, oxidation of cardiolipin; oxidation of protein sulfhydryls; depletion of the non-enzymatic antioxidant defense and increased activity of caspase-3. Carvedilol per se did not present any effect on renal mitochondria. It was concluded that carvedilol prevents mitochondrial dysfunction and renal cell death through the protection against the oxidative stress and redox state unbalance induced by cisplatin. The association of carvedilol to cisplatin chemotherapy was suggested as a possible strategy to minimize the nephrotoxicity induced by this antitumor agent.
顺铂是一种高效的化疗药物，会导致严重的肾毒性。研究表明，活性氧物质主要在线粒体中产生，在顺铂诱导的肾损伤中起核心作用。大量的抗氧化剂已被评估为预防顺铂诱导的肾毒性的可能保护剂；然而，尚未发现安全有效的化合物。本研究首次评估了卡维地洛（一种具有强大抗氧化特性的β受体阻滞剂）对顺铂治疗大鼠肾脏线粒体氧化应激和细胞凋亡的保护潜力。卡维地洛可预防以下顺铂引起的毒性作用：血浆肌酐和血尿素氮（BUN）水平升高；脂质过氧化，心磷脂氧化；蛋白质巯基氧化；非酶抗氧化防御的耗竭以及 caspase-3 活性增加。卡维地洛本身对肾脏线粒体没有任何影响。结论是，卡维地洛通过防止顺铂诱导的氧化应激和氧化还原状态失衡来预防线粒体功能障碍和肾细胞死亡。建议将卡维地洛与顺铂化疗联合使用，作为降低这种抗肿瘤药物肾毒性的一种可能策略。
