MDM2 inhibitor ameliorates cisplatin-induced nephropathy via NF kappa B signal inhibition

Fujikura, Tomoyuki; Yasuda, Hideo; Iwakura, Takamasa; Tsuji, Takayuki und Anders, Hans-Joachim (2019): MDM2 inhibitor ameliorates cisplatin-induced nephropathy via NF kappa B signal inhibition. In: Pharmacology Research & Perspectives, Bd. 7, Nr. 1, UNSP e00450

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-kappa B (NF kappa B), 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 NF kappa B 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 NF kappa B 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 NF kappa B transcriptional activity. DS-5272 co-treatment reduced both cisplatin-induced cell death and NF kappa B transcriptional activity. Collectively, these findings suggest that DS-5272 can ameliorate cisplatin nephrotoxicity via NF kappa B signal inhibition.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2052-1707
• Sprache: Englisch