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

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

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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 reno-protection 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.

Original languageEnglish (US)
Pages (from-to)2709-2722
Number of pages14
JournalJournal of Clinical Investigation
Volume121
Issue number7
DOIs
StatePublished - Jul 1 2011

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Cisplatin
Neoplasms
Kidney
Drug Therapy
Apoptosis
Heterografts
Cell Death
Cell Line
Therapeutics
Research

ASJC Scopus subject areas

  • Medicine(all)

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Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer. / Pabla, Navjotsingh; Dong, Guie; Livingston, Man Jiang; Huang, Shuang; Kumar, M. Vijay; Messing, Robert O.; Dong, Zheng.

In: Journal of Clinical Investigation, Vol. 121, No. 7, 01.07.2011, p. 2709-2722.

Research output: Contribution to journalArticle

Pabla, Navjotsingh ; Dong, Guie ; Livingston, Man Jiang ; Huang, Shuang ; Kumar, M. Vijay ; Messing, Robert O. ; Dong, Zheng. / Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 7. pp. 2709-2722.
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