HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 286/2/F378    most recent 00192.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (22) Citing Articles via Google Scholar Google Scholar Articles by Price, P. M. Articles by Megyesi, J. Search for Related Content PubMed PubMed Citation Articles by Price, P. M. Articles by Megyesi, J.

Protection of renal cells from cisplatin toxicity by cell cycle inhibitors

Department of Internal Medicine, University of Arkansas for Medical Sciences, and Department of Veterans Affairs Medical Center, Little Rock, Arkansas 72205

Submitted 19 May 2003 ; accepted in final form 2 September 2003

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 are also upregulated. 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 before acute renal failure could protect from cisplatin-induced cell death, especially in cells with functional p21 and 14-3-3 genes. Using several cell cycle inhibitors, including a p21 adenovirus, and the drugs roscovitine and olomoucine, we have been able to completely protect a mouse kidney proximal tubule cell culture from cisplatin-induced apoptosis. The protection by p21 was independent of an effect on the cell cycle and was likely caused by selective inhibition of caspase-dependent and -independent cell death pathways in the cells.

kidney failure; p21 cyclin kinase inhibitor; roscovitine

This article has been cited by other articles:

				E. Garner, F. Martinon, J. Tschopp, P. Beard, and K. Raj Cells with Defective p53-p21-pRb Pathway Are Susceptible to Apoptosis Induced by p84N5 via Caspase-6 Cancer Res., August 15, 2007; 67(16): 7631 - 7637. [Abstract] [Full Text] [PDF]

				F. Yu, J. Megyesi, R. L. Safirstein, and P. M. Price Involvement of the CDK2-E2F1 pathway in cisplatin cytotoxicity in vitro and in vivo Am J Physiol Renal Physiol, July 1, 2007; 293(1): F52 - F59. [Abstract] [Full Text] [PDF]

				P. M. Price, F. Yu, P. Kaldis, E. Aleem, G. Nowak, R. L. Safirstein, and J. Megyesi Dependence of Cisplatin-Induced Cell Death In Vitro and In Vivo on Cyclin-Dependent Kinase 2 J. Am. Soc. Nephrol., September 1, 2006; 17(9): 2434 - 2442. [Abstract] [Full Text] [PDF]

				H. Zhou, Y. Fujigaki, A. Kato, T. Miyaji, H. Yasuda, T. Tsuji, T. Yamamoto, K. Yonemura, and A. Hishida Inhibition of p21 modifies the response of cortical proximal tubules to cisplatin in rats Am J Physiol Renal Physiol, July 1, 2006; 291(1): F225 - F235. [Abstract] [Full Text] [PDF]

				E. Sohara, T. Rai, J.-i. Miyazaki, A. S. Verkman, S. Sasaki, and S. Uchida Defective water and glycerol transport in the proximal tubules of AQP7 knockout mice Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1195 - F1200. [Abstract] [Full Text] [PDF]

				K. A. Nath Provenance of the protective property of p21 Am J Physiol Renal Physiol, September 1, 2005; 289(3): F512 - F513. [Full Text] [PDF]

				F. Yu, J. Megyesi, R. L. Safirstein, and P. M. Price Identification of the functional domain of p21WAF1/CIP1 that protects cells from cisplatin cytotoxicity Am J Physiol Renal Physiol, September 1, 2005; 289(3): F514 - F520. [Abstract] [Full Text] [PDF]

				G. Ramesh and W. B. Reeves p38 MAP kinase inhibition ameliorates cisplatin nephrotoxicity in mice Am J Physiol Renal Physiol, July 1, 2005; 289(1): F166 - F174. [Abstract] [Full Text] [PDF]

				M. Jiang, X. Yi, S. Hsu, C.-Y. Wang, and Z. Dong Role of p53 in cisplatin-induced tubular cell apoptosis: dependence on p53 transcriptional activity Am J Physiol Renal Physiol, December 1, 2004; 287(6): F1140 - F1147. [Abstract] [Full Text] [PDF]

				I. Arany, J. K. Megyesi, H. Kaneto, P. M. Price, and R. L. Safirstein Cisplatin-induced cell death is EGFR/src/ERK signaling dependent in mouse proximal tubule cells Am J Physiol Renal Physiol, September 1, 2004; 287(3): F543 - F549. [Abstract] [Full Text] [PDF]

				K. Hiromura and S. J. Shankland Negatively Regulating the Cell Cycle Can Be Positive J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1361 - 1362. [Full Text] [PDF]