Dugbartey George J, Peppone Luke J, de Graaf Inge A M
Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States; Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Department of Surgery, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY, United States.
Toxicology. 2016 Sep 14;371:58-66. doi: 10.1016/j.tox.2016.10.001. Epub 2016 Oct 4.
Cisplatin is currently one of the most widely-used chemotherapeutic agents against various malignancies. Its clinical application is limited, however, by inherent renal and cardiac toxicities and other side effects, of which the underlying mechanisms are only partly understood. Experimental studies show cisplatin generates reactive oxygen species, which impair the cell's antioxidant defense system, causing oxidative stress and potentiating injury, thereby culminating in kidney and heart failure. Understanding the molecular mechanisms of cisplatin-induced renal and cardiac toxicities may allow clinicians to prevent or treat this problem better and may also provide a model for investigating drug-induced organ toxicity in general. This review discusses some of the major molecular mechanisms of cisplatin-induced renal and cardiac toxicities including disruption of ionic homeostasis and energy status of the cell leading to cell injury and cell death. We highlight clinical manifestations of both toxicities as well as (novel)biomarkers such as kidney injury molecule-1 (KIM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). We also present some current treatment challenges and propose potential protective strategies including combination therapy with novel pharmacological compounds that might mitigate or prevent these toxicities, which include the use of hydrogen sulfide.
顺铂是目前针对各种恶性肿瘤应用最广泛的化疗药物之一。然而，其临床应用受到固有的肾毒性、心脏毒性及其他副作用的限制，其潜在机制仅部分为人所知。实验研究表明，顺铂会产生活性氧，损害细胞的抗氧化防御系统，导致氧化应激并加重损伤，最终导致肾衰竭和心力衰竭。了解顺铂诱导的肾毒性和心脏毒性的分子机制，可能使临床医生更好地预防或治疗这一问题，也可能为一般药物诱导的器官毒性研究提供一个模型。本综述讨论了顺铂诱导的肾毒性和心脏毒性的一些主要分子机制，包括离子稳态破坏和细胞能量状态改变导致细胞损伤和死亡。我们重点介绍了这两种毒性的临床表现以及（新型）生物标志物，如肾损伤分子-1（KIM-1）、金属蛋白酶组织抑制剂-1（TIMP-1）和N端前B型利钠肽（NT-proBNP）。我们还介绍了当前的一些治疗挑战，并提出了潜在的保护策略，包括与新型药理化合物联合治疗，这些化合物可能减轻或预防这些毒性，其中包括使用硫化氢。
