Pourahmad Jalal, Hosseini Mir-Jamal, Eskandari Mohammad Reza, Shekarabi Seyed Mohammad, Daraei Bahram
Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.
Xenobiotica. 2010 Nov;40(11):763-71. doi: 10.3109/00498254.2010.512093.
Cisplatin is widely used chemotherapeutic agent for the treatment of several human malignancies. Dose-related nephrotoxicity is the major adverse effect of cisplatin. The cellular and molecular mechanisms behind the cisplatin nephrotoxicity have not yet been completely understood. In this study, cytotoxic effect of cisplatin on renal proximal tubular (RPT) cells was evaluated. Our results showed that cytotoxic action of cisplatin on RPT cells is mediated by reactive oxygen species (ROS) formation, decline of mitochondrial membrane potential, increase in caspase-3 activity and lysosomal membrane leakiness before cell lysis ensued. All of the above mentioned cisplatin-induced oxidative stress cytotoxicity markers were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, mitochondrial permeability transition (MPT) pore sealing agents, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Our results also showed that CYP2E1 involves in cisplatin oxidative stress cytotoxicity mechanism and intracellular nitric oxide enhancement protects the RPT cells against the cisplatin-induced cytotoxicity. It seems that cisplatin nephrotoxicity is associated with mutual mitochondrial/lysosomal potentiation (cross-talk) of oxidative stress in RPT cells. This cross-talk finally results in release of lysosomal digestive proteases and phospholipases and mitochondrial MPT pore opening leading to cytochrome c release and activation of caspases cascade which signal apoptosis.
顺铂是一种广泛用于治疗多种人类恶性肿瘤的化疗药物。与剂量相关的肾毒性是顺铂的主要不良反应。顺铂肾毒性背后的细胞和分子机制尚未完全明确。在本研究中，评估了顺铂对肾近端小管（RPT）细胞的细胞毒性作用。我们的结果表明，顺铂对RPT细胞的细胞毒性作用是由活性氧（ROS）生成、线粒体膜电位下降、细胞裂解前caspase-3活性增加和溶酶体膜渗漏介导的。上述所有顺铂诱导的氧化应激细胞毒性标志物均被ROS清除剂、抗氧化剂、线粒体通透性转换（MPT）孔封闭剂、内吞作用抑制剂和三磷酸腺苷（ATP）生成剂显著（p＜0.05）抑制。我们的结果还表明，CYP2E1参与顺铂氧化应激细胞毒性机制，细胞内一氧化氮增强可保护RPT细胞免受顺铂诱导的细胞毒性。顺铂肾毒性似乎与RPT细胞中氧化应激的线粒体/溶酶体相互增强（相互作用）有关。这种相互作用最终导致溶酶体消化蛋白酶和磷脂酶的释放以及线粒体MPT孔开放，导致细胞色素c释放和caspase级联激活，从而引发细胞凋亡信号。
