Mechanisms of death induced by cisplatin in proximal tubular epithelial cells: apoptosis vs. necrosis

Abstract

We have examined the mechanisms of cell death induced by cisplatin in primary cultures of mouse proximal tubular cells. High concentrations of cisplatin (800 microM) led to necrotic cell death over a few hours. Much lower concentrations of cisplatin (8 microM) led to apoptosis, which caused loss of the cell monolayer over several days. Necrosis was characterized by a cytosolic swelling and early loss of plasma membrane integrity. In contrast, early features of cells undergoing apoptosis included cell shrinkage and loss of attachment to the monolayers. Nuclear chromatin became condensed and fragmented in apoptosing cells. These features were absent in necrotic cells. DNA electrophoresis of cells exposed to 800 microM cisplatin yielded a "smear" pattern, due to random DNA degradation. In contrast, the DNA of apoptosing cells demonstrated a "ladder" pattern resulting from internucleosomal DNA cleavage. Antioxidants delayed cisplatin-induced apoptosis but not necrosis. Thus the mechanism of cell death induced by cisplatin is concentration dependent. Reactive oxygen species play a role in mediating apoptosis but not necrosis induced by cisplatin.

New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy

“…Cisplatin was observed to induce apoptosis at low doses, but necrosis at high doses in mouse renal epithelial cells (Lieberthal et al, 1996). This was similarly observed for cyclosporin (Healy et al, 1998).…”

The anticancer drug cisplatin induces an intrinsic apoptotic pathway inside the inner ear

“…Another emerging problem concerning the use of high doses of cisplatin is the different cell death-induced pattern; at lower doses, the proapoptotic initiator caspases-8 and caspase-9, and the executioner caspase-3 are activated and result in apoptosis. In contrast, higher doses of cisplatin are accompanied by a decline in caspase-3 activity and widespread cell necrosis (Lieberthal et al, 1996).…”

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

“…For instance, primary cultures of mouse proximal tubule cells underwent necrotic death after exposure to high concentrations of cisplatin (800 μmol/l) for a few hours, whereas apoptosis was induced following exposure to lower concentrations of cisplatin (8 μmol/l) over a few days [36]. The association of nongenic SNPs with apoptosis may indicate locations of new binding sites, such as for p53, regulating cisplatin-induced apoptosis or gene expression [32].…”