Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
Life Sci. 2019 Feb 1;218:112-131. doi: 10.1016/j.lfs.2018.12.018. Epub 2018 Dec 12.
Cyclophosphamide (CP) is an important anticancer drug which belongs to the class of alkylating agent. Cyclophosphamide is mostly used in bone marrow transplantation, rheumatoid arthritis, lupus erythematosus, multiple sclerosis, neuroblastoma and other types of cancer. Dose-related cardiotoxicity is a limiting factor for its use. CP-induced cardiotoxicity ranges from 7 to 28% and mortality ranges from 11 to 43% at the therapeutic dose of 170-180 mg/kg, i.v. CP undergoes hepatic metabolism that results in the production of aldophosphamide. Aldophosphamide decomposes into phosphoramide mustard & acrolein. Phosphoramide is an active neoplastic agent, and acrolein is a toxic metabolite which acts on the myocardium and endothelial cells. This is the first review article that talks about cyclophosphamide-induced cardiotoxicity and the different signaling pathways involved in its pathogenicity. Based on the available literature, CP is accountable for cardiomyocytes energy pool alteration by affecting the heart fatty acid binding proteins (H-FABP). CP has been found associated with cardiomyocytes apoptosis, inflammation, endothelial dysfunction, calcium dysregulation, endoplasmic reticulum damage, and mitochondrial damage. Molecular mechanism of cardiotoxicity has been discussed in detail through crosstalk of Nrf2/ARE, Akt/GSK-3β/NFAT/calcineurin, p53/p38MAPK, NF-kB/TLR-4, and Phospholamban/SERCA-2a signaling pathway. Based on the available literature we support the fact that metabolites of CP are responsible for cardiotoxicity due to depletion of antioxidants/ATP level, altered contractility, damaged endothelium and enhanced pro-inflammatory/pro-apoptotic activities resulting into cardiomyopathy, myocardial infarction, and heart failure. Dose adjustment, elimination/excretion of acrolein and maintenance of endogenous antioxidant pool could be the therapeutic approach to mitigate the toxicities.
环磷酰胺（CP）是一种重要的抗癌药物，属于烷化剂类。环磷酰胺主要用于骨髓移植、类风湿性关节炎、红斑狼疮、多发性硬化、神经母细胞瘤和其他类型的癌症。剂量相关的心脏毒性是其使用的限制因素。在治疗剂量为 170-180mg/kg、静脉注射时，CP 引起的心脏毒性范围为 7%至 28%，死亡率范围为 11%至 43%。CP 在肝脏代谢生成醛磷酰胺。醛磷酰胺分解为磷酰胺氮芥和丙烯醛。磷酰胺是一种活性抗肿瘤剂，丙烯醛是一种有毒代谢物，作用于心肌和内皮细胞。这是第一篇讨论环磷酰胺诱导的心脏毒性及其在发病机制中涉及的不同信号通路的综述文章。根据现有文献，CP 通过影响心脏脂肪酸结合蛋白（H-FABP）来改变心肌细胞的能量池。CP 与心肌细胞凋亡、炎症、内皮功能障碍、钙调节异常、内质网损伤和线粒体损伤有关。通过 Nrf2/ARE、Akt/GSK-3β/NFAT/calcineurin、p53/p38MAPK、NF-kB/TLR-4 和 Phospholamban/SERCA-2a 信号通路的相互作用，详细讨论了心脏毒性的分子机制。根据现有文献，我们支持 CP 的代谢物由于抗氧化剂/ATP 水平的耗竭、收缩性改变、受损的内皮和增强的促炎/促凋亡活性导致心肌病、心肌梗死和心力衰竭而导致心脏毒性的事实。调整剂量、消除/排泄丙烯醛和维持内源性抗氧化剂池可能是减轻毒性的治疗方法。
