Inhibition of PKC? 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 PKC? 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 PKC? in mouse kidney lysates. After activation, PKC? regulated MAPKs, but not p53, to induce renal cell apoptosis. Thus, inhibition of PKC? pharmacologically or genetically attenuated kidney cell apoptosis and tissue damage, preserving renal function during cisplatin treatment. Conversely, inhibition of PKC? 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 PKC? in cisplatin nephrotoxicity and support targeting PKC? as an effective strategy for renoprotection during cisplatin-based cancer therapy.

SUBMITTER: Pabla N 

PROVIDER: S-EPMC3223835 | biostudies-other | 2011 Jul

REPOSITORIES: biostudies-other