Abd El-Rhman Rana H, El-Naga Reem N, Gad Amany M, Tadros Mariane G, Hassaneen Sherifa K
Department of Pharmacology, Egyptian Drug Authority (ED), Giza, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Front Pharmacol. 2020 Dec 14;11:567852. doi: 10.3389/fphar.2020.567852. eCollection 2020.
Cisplatin is one of the standard anti-cancer agents that are used to treat variety of solid tumors. Nevertheless, due to the accumulation of cisplatin in the renal epithelial cells, nephrotoxicity was found to be the main side effect that limits its clinical use. The current study was conducted to assess the potential nephroprotective effect of dibenzazepine, a Notch inhibitor, against cisplatin-induced nephrotoxicity in rats as well as the possible mechanisms underlying this nephroprotection. The rats were pre-treated with 2 mg/kg dibenzazepine for 7 days before giving a single nephrotoxic dose of cisplatin (7 mg/kg). Cisplatin induced acute nephrotoxicity, where blood urea nitrogen and serum creatinine levels were significantly increased. Besides, lipid peroxidation was markedly elevated and the levels of reduced glutathione and catalase were significantly reduced. Also, the tissue levels of the pro-inflammatory mediators; IL-1β, TNF-α, and NF-kB, were significantly increased in the cisplatin group. The pre-treatment with dibenzazepine significantly mitigated the nephrotoxic effects of cisplatin, the oxidative stress and inflammatory status as well as decreased caspase-3 expression, as compared to the cisplatin group. Furthermore, the up-regulation of Notch-1 and Hes-1 was found to be involved in cisplatin-induced nephrotoxicity and their expression was significantly reduced by dibenzazepine. The nephroprotective effect of dibenzazepine was further confirmed by the histopathological assessment. Moreover, dibenzazepine pre-treatment of hela and PC3 cells did not antagonize the cisplatin anti-cancer activity. In conclusion, these findings show that dibenzazepine provides protection against cisplatin-induced nephrotoxicity. Moreover, the up-regulation of the Notch pathway was shown to play a role in the pathogenesis of cisplatin-induced renal injury.
顺铂是用于治疗多种实体瘤的标准抗癌药物之一。然而，由于顺铂在肾上皮细胞中的蓄积，肾毒性被发现是限制其临床应用的主要副作用。本研究旨在评估Notch抑制剂二苯并氮杂䓬对顺铂诱导的大鼠肾毒性的潜在肾保护作用及其潜在机制。在给予单次肾毒性剂量的顺铂（7mg/kg）前7天，大鼠用2mg/kg二苯并氮杂䓬进行预处理。顺铂诱导急性肾毒性，血尿素氮和血清肌酐水平显著升高。此外，脂质过氧化明显升高，还原型谷胱甘肽和过氧化氢酶水平显著降低。而且，顺铂组促炎介质IL-1β、TNF-α和NF-κB的组织水平显著升高。与顺铂组相比，二苯并氮杂䓬预处理显著减轻了顺铂的肾毒性作用、氧化应激和炎症状态，并降低了caspase-3表达。此外，发现Notch-1和Hes-1的上调参与顺铂诱导的肾毒性，二苯并氮杂䓬显著降低了它们的表达。组织病理学评估进一步证实了二苯并氮杂䓬的肾保护作用。此外，二苯并氮杂䓬对hela和PC3细胞的预处理并未拮抗顺铂的抗癌活性。总之，这些发现表明二苯并氮杂䓬可预防顺铂诱导的肾毒性。此外，Notch通路的上调在顺铂诱导的肾损伤发病机制中起作用。
