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1 Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Veterans Affairs Medical Center, University of Arkansas for Medical Sciences, Little Rock, AR, USA
* To whom correspondence should be addressed. E-mail: pricepeterm{at}uams.edu.
The optimal use of cisplatin as a chemotherapeutic drug has been limited by its nephrotoxicity. Murine models have been used to study cisplatin-induced acute renal failure. After cisplatin administration, cells of the S3 segment in the renal proximal tubule are especially sensitive, and undergo extensive necrosis in vivo. Similarly, cultured proximal tubule cells undergo apoptosis in vitro after cisplatin exposure. We have shown in vivo that kidney cells enter the cell cycle after cisplatin administration, but that cell cycle inhibitory proteins, p21 and 14-3-3
, were also up-regulated. These proteins coordinate the cell cycle and deletion of either of the genes resulted in increased nephrotoxicity in vivo or increased cell death in vitro after exposure to cisplatin. However, it was not known whether cell cycle inhibition prior to acute renal failure could protect from cisplatin-induced cell death, especially in cells with functional p21 and 14-3-3 genes. We have now used several cell cycle inhibitors, including a p21-adenovirus, and the drugs roscovitine and olomoucine, and have been able to completely protect from cisplatin-induced apoptosis in a mouse kidney proximal tubule cell culture. The protection by p21 was independent of an effect on the cell cycle, and was likely caused by selective inhibition of both caspase-dependent and -independent cell death pathways in the cells.
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