Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation

Man Jiang Livingston, Navjotsin Pabla, Robert F. Murphy, Tianxin Yang, Xiao Ming Yin, Kurt Degenhardt, Eileen White, Zheng Dong

Research output: Contribution to journalArticle

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Abstract

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. Onthe 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.

Original languageEnglish (US)
Pages (from-to)2636-2645
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number4
DOIs
StatePublished - Jan 26 2007

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Cisplatin
Chemical activation
Kidney
Apoptosis
Oligomerization
Chemotherapy
Cytochromes c
Pharmaceutical Preparations
Therapeutics
Drug Therapy
Mitochondria
Drug-Related Side Effects and Adverse Reactions
Gene expression
Hand
Cells
nutlin 3
Pharmacology
Tissue
Gene Expression
Peptides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation. / Livingston, Man Jiang; Pabla, Navjotsin; Murphy, Robert F.; Yang, Tianxin; Yin, Xiao Ming; Degenhardt, Kurt; White, Eileen; Dong, Zheng.

In: Journal of Biological Chemistry, Vol. 282, No. 4, 26.01.2007, p. 2636-2645.

Research output: Contribution to journalArticle

Livingston, Man Jiang ; Pabla, Navjotsin ; Murphy, Robert F. ; Yang, Tianxin ; Yin, Xiao Ming ; Degenhardt, Kurt ; White, Eileen ; Dong, Zheng. / Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 4. pp. 2636-2645.
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