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Dependence of Cisplatin-Induced Cell Death In Vitro and In Vivo on Cyclin-Dependent Kinase 2

Peter M. Price^*,, Fang Yu, Philipp Kaldis, Eiman Aleem, Grayna Nowak, Robert L. Safirstein^*, and Judit Megyesi^*,

Departments of ^* Internal Medicine, Physiology, and Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland

Address correspondence to: Dr. Peter M. Price, Department of Medicine, University of Arkansas for Medical Sciences, VA Medical Center-Research Section, 4300 West 7th Street, Room GC 147, Little Rock, AR 72205. Phone: 501-257-4800; Fax: 501-257-4822; E-mail: PricePeterM{at}uams.edu

Received for publication February 21, 2006. Accepted for publication June 29, 2006.

Cisplatin is one of the most effective chemotherapeutics, but its usefulness is limited by its toxicity to normal tissues, including cells of the kidney proximal tubule. The purpose of these studies was to determine the mechanism of cisplatin cytotoxicity. It was shown in vivo that cisplatin administration induces upregulation of the gene for the p21 cyclin-dependent kinase (cdk) inhibitor in kidney cells. This protein is a positive effector on the fate of cisplatin-exposed renal tubule cells in vivo and in vitro; adenoviral transduction of p21 completely protected proximal tubule cells from cisplatin toxicity. Herein is reported that cdk2 inhibitory drugs protect kidney cells in vivo and in vitro, that transduction of kidney cells in vitro with dominant-negative cdk2 also protected, and that cdk2 knockout cells were resistant to cisplatin. The cdk2 knockout cells regained cisplatin sensitivity after transduction with wild-type cdk2. It is concluded that cisplatin cytotoxicity depends on cdk2 activation and that the mechanism of p21 protection is by direct inhibition of cdk2. This demonstrated the involvement of a protein that previously was associated with cell-cycle progression with pathways of apoptosis. It also was demonstrated that this pathway of cisplatin-induced cell death can be interceded in vivo to prevent nephrotoxicity.

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