Abstract
Cisplatin is a platinum‐containing chemotherapeutic drug, which is widely used and highly effective. While effective against tumors, its use is limited by severe side effects such as nephrotoxicity and bone marrow suppression. Murine double minute 2 (MDM2) is the E3 ubiquitin ligase of the tumor suppressor gene, p53, and inhibition of MDM2 can suppress tumor cell growth. However, independent of p53, MDM2 acts as a co‐transcription factor for nuclear factor‐κB (NFκB), whose signaling can be involved in cisplatin‐induced tubular injury. We therefore examined the effects of MDM2 inhibitor on cisplatin cytotoxicity. In order to induce acute kidney injury and to investigate MDM2 inhibitory effects, we injected cisplatin into rats with or without the MDM2 inhibitor, DS‐5272, and analyzed kidney physiology/histology and NFκB signaling. Serum creatinine was significantly lower in the DS‐5272 group than in the vehicle group on day 3 (0.55 ± 0.069 vs 0.70 ± 0.072 mg/dL, P < 0.05). DS‐5272 also significantly decreased kidney injury molecule‐1 (KIM‐1) expression, improved tubular injury, and decreased apoptotic cells. Western blotting showed that cisplatin increased NFκB phosphorylation in kidneys, which was significantly suppressed by DS‐5272. In vitro, we treated HEK 293 cells with cisplatin, in the absence or presence of DS‐5272, and examined cytotoxicity and NFκB transcriptional activity. DS‐5272 co‐treatment reduced both cisplatin‐induced cell death and NFκB transcriptional activity. Collectively, these findings suggest that DS‐5272 can ameliorate cisplatin nephrotoxicity via NFκB signal inhibition.
Highlights
Cisplatin (cis‐diamminedichloro‐platinum (II)) is a platinum‐containing cancer therapy drug, that is widely used and highly effective
We investigated the effect of the Murine double minute 2 (MDM2) inhibitor, DS‐ 5272, on cisplatin‐induced kidney injury and the mechanism involved
The results demonstrated that cisplatin caused structural and functional kidney injury in association with increased nuclear factor‐κB (NFκB) activation and that DS‐5272 ameliorated these cisplatin‐induced kidney injuries and suppressed NFκB phosphorylation
Summary
Cisplatin (cis‐diamminedichloro‐platinum (II)) is a platinum‐containing cancer therapy drug, that is widely used and highly effective. Murine double minute 2 (MDM2) is the E3 ubiquitin ligase of the tumor suppressor gene, p53, and acts as a co‐transcription factor for nuclear factor‐κB (NFκB).[2] MDM2 inhibitor exhibits no toxicity against normal tissue, but it can function as a cancer therapy drug that assembles p53 and induces cancer cell death.[3] combination therapy of MDM2 inhibitor and cisplatin may have synergistic effects.[4,5,6] MDM2 inhibitor has been reported to suppress cell apoptosis induced by cisplatin in vitro.[7] The inhibition of p53 or NFκB signaling has been shown to improve acute kidney injury induced by cisplatin.[8,9,10,11] the effects of MDM2 inhibitor on cisplatin‐exposed normal tubular and cancerous cells may be different. We induced nephropathy in vivo or tubular‐ cell death in vitro with cisplatin and analyzed the effects of MDM2 inhibitor on this toxicity and on NFκB signaling
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