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J. Biol. Chem., Vol. 282, Issue 4, 2636-2645, January 26, 2007

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Nutlin-3 Protects Kidney Cells during Cisplatin Therapy by Suppressing Bax/Bak Activation^*

Man Jiang, Navjotsin Pabla, Robert F. Murphy, Tianxin Yang^¶, Xiao-Ming Yin^||, Kurt Degenhardt^**, Eileen White^**, and Zheng Dong¹

From the Department of Cellular Biology and Anatomy, Medical College of Georgia and Veterans Affairs Medical Center, Augusta, Georgia 30912, the NCI, National Institutes of Health, Bethesda, Maryland 20982, the ^¶Department of Internal Medicine, University of Utah, Salt Lake City, Utah 84148, the ^||Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, and the ^**Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers University, Cancer Institute of New Jersey, Piscataway, New Jersey 08854

Nutlins, the newly developed small molecule antagonists of MDM2, activate p53 and induce apoptosis in cancer cells, offering a novel strategy of chemotherapy. Recent studies have further suggested synergistic effects of nutlins with other chemotherapeutic drugs. However, it is unclear whether nutlins increase or decrease the side effects of these drugs in normal non-malignant cells or tissues. Cisplatin is a widely used chemotherapy drug, which has a major side effect of kidney injury. Here we show that Nutlin-3 protected kidney cells against cisplatin-induced apoptosis. The cytoprotective effects of Nutlin-3 were not related to its regulation of p53 or consequent gene expression during cisplatin treatment. Moreover, the protective effects were shown in MDM2-, MDM4-, or p53-deficient cells. On the other hand, Nutlin-3 suppressed mitochondrial events of apoptosis during cisplatin incubation, including Bax activation and cytochrome c release. Nutlin-3 attenuated cisplatin-induced oligomerization of Bax and Bak but not their interactions with Bcl-XL. In isolated mitochondria, Nutlin-3 inhibited cytochrome c release induced by Ca²⁺, Bim peptide, and recombinant tBid. Importantly, it blocked both Bax and Bak oligomerization under these conditions. Together, the results have uncovered a new pharmacological function of nutlins, i.e. suppression of Bax and Bak, two critical mediators of apoptosis.

Received for publication, July 20, 2006 , and in revised form, November 21, 2006.

^* This work was supported by grants from the National Institutes of Health and the U. S. Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Cellular Biology and Anatomy, Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA 30912. Tel.: 706-721-2825; Fax: 706-721-6120; E-mail: zdong{at}mail.mcg.edu.

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