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

Abstract

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.

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

“…The activation of apoptosis occurs through a mitochondrial membrane potential change and caspase-3 activation 37,38 . Our results support these findings showing that Pt14-Pt16 induces apoptosis in MCF-7 and MDA-MB-231 cells through changing mitochondrial membrane potential.…”

The Endolysosomal System in Cell Death and Survival

“…Zhao et al (2001) suggested that short stimulation with hydrogen peroxide could also trigger LMP indirectly by activation of phospholipase A2, leading to degradation of membrane phospholipids. Importantly, several stimuli, such as the aminoglycoside antibiotic gentamicin (Denamur et al 2011), the s2 receptor ligand siramesine (Ostenfeld et al 2005), and the widely used chemotherapeutic agent cisplatin (Pourahmad et al 2010), were also linked to increased ROS production, leading to LMP. Finally, oxidative stress and ROS-dependent LMP were suggested to be especially important in the aging of postmitotic cells (Kurz et al 2007).…”

Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction

“…The utilized doses for ROS scavengers (butylated hydroxytoluen (BHT) and α-tocopherol succinate), MPT pore sealing agents (trifluoperazine and carnitine), ATP generators (l-glutamine and fructose), lysosomotropic agents (methylamine and chloroquine) and CYP450 inhibitors (cimetidine and 4-methylpyrazole) were chosen from similar experiments that were done on rat hepatocytes. [24][25][26] We also investigated the aforementioned doses in our isolation system and perceived that they have maximal protective impacts on the cytotoxicity indicators (data not shown).…”

“…32,33 To do the experiment, a volume of 0.5 ml of the pre-stained (acridine orange 5 μM) cell suspension was taken and centrifuged at 800× g for 1min. Thereafter, the cell pellet was resuspended in 2ml of incubation medium.…”