Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer
Navjotsingh Pabla, … , Robert O. Messing, Zheng Dong
Navjotsingh Pabla, … , Robert O. Messing, Zheng Dong
Published June 1, 2011
Citation Information: J Clin Invest. 2011;121(7):2709-2722. https://doi.org/10.1172/JCI45586.
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Research Article Nephrology

Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

Abstract

Cisplatin is a widely used cancer therapy drug that unfortunately has major side effects in normal tissues, notably nephrotoxicity in kidneys. Despite intensive research, the mechanism of cisplatin-induced nephrotoxicity remains unclear, and renoprotective approaches during cisplatin-based chemotherapy are lacking. Here we have identified PKCδ as a critical regulator of cisplatin nephrotoxicity, which can be effectively targeted for renoprotection during chemotherapy. We showed that early during cisplatin nephrotoxicity, Src interacted with, phosphorylated, and activated PKCδ in mouse kidney lysates. After activation, PKCδ regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKCδ pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKCδ enhanced cisplatin-induced cell death in multiple cancer cell lines and, remarkably, enhanced the chemotherapeutic effects of cisplatin in several xenograft and syngeneic mouse tumor models while protecting kidneys from nephrotoxicity. Together these results demonstrate a role of PKCδ in cisplatin nephrotoxicity and support targeting PKCδ as an effective strategy for renoprotection during cisplatin-based cancer therapy.

Authors

Navjotsingh Pabla, Guie Dong, Man Jiang, Shuang Huang, M. Vijay Kumar, Robert O. Messing, Zheng Dong

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Figure 11

PKCδ inhibitor δV1-1 protect kidneys while enhancing cisplatin chemotherapy in human testicular and breast cancer tumor xenograft models.

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PKCδ inhibitor δV1-1 protect kidneys while enhancing cisplatin chemother...
(A and B) Human NCCIT testicular cancer cells were injected into the flanks of 6- to 8-week-old male nude mice to monitor tumor growth. In 2 weeks, the tumor volume increased to approximately 200 mm3, and the mice were divided into 5 groups (10 mice/group) for following treatments: saline (untreated), 20 mg/kg cisplatin, 20 mg/kg cisplatin plus 10 mg/kg rottlerin, 20 mg/kg cisplatin plus 3 mg/kg Tat peptide, and 20 mg/kg cisplatin plus 3 mg/kg δV1-1 peptide. Cisplatin and rottlerin were injected (i.p.) weekly. Tat and δV1-1 were injected (i.p.) biweekly. (A) Tumor volume. (B) BUN levels. (C and D) Human MDA-231 breast cancer cells were injected into the flanks of female nude mice. After the tumors grew to approximately 700 mm3, the mice were treated with 10 mg/kg cisplatin plus 3 mg/kg Tat or 10 mg/kg cisplatin plus 3 mg/kg δV1-1. (C) Tumor volume and (D) BUN levels were measured at indicated times. Mean ± SD, n = 6–10. *P < 0.05 versus untreated saline control group; ‡P < 0.05 versus week 0; #P < 0.05 versus cisplatin-only group; §P < 0.05 versus cisplatin plus Tat group.