Mitochondrial/lysosomal toxic cross-talk plays a key role in cisplatin nephrotoxicity

Abstract

1. 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.

2. 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.

3. 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.

Keywords::

• Cisplatin
• nephrotoxicity
• renal proximal tubular (RPT) cells
• oxidative stress
• mitochondrial/lysosomal cross-talk

Acknowledgments

The results presented in this article were partly extracted from thesis of Dr. Seyed Mohammad Shekarabi (Pham.D. graduate of Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences) who performed his thesis under supervision of Prof. Jalal Pourahmad. The investigations were performed in Professor J. Pourahmad’s laboratory at Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.

Declaration of interest

This research was financially supported by a research grant from the Shaheed Beheshti University of Medical Sciences, Deputy of Research (Grant No: 167-85/9/26). The authors state no conflicts of interest.