Fan Jiaojiao, Xu Xinyue, Li Yuting, Zhang Lingge, Miao Mengqiu, Niu Yujia, Zhang Yue, Zhang Aihua, Jia Zhanjun, Wu Mengqiu
School of Medicine, Southeast University, Nanjing, 210009, China; Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing, 210029, China.
Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China; Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
Free Radic Biol Med. 2023 Jan;194:84-98. doi: 10.1016/j.freeradbiomed.2022.11.029. Epub 2022 Nov 18.
Cisplatin is one of the most effective chemotherapy drugs and is widely used for cancer treatment. However, its clinical use is limited by nephrotoxicity. Emerging findings suggested that both ferroptosis and mitochondrial dysfunction mediate cisplatin-induced nephrotoxicity. In the current study, a novel 3-phenylglutaric acid derivative 5-[[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]amino]-5-oxo-3-phenylpentanoic acid (referred to as 84-B10) was found to play a protective role in cisplatin-induced acute kidney injury with no tumor promoting effects. A genome-wide transcriptome analysis indicated that the protective effect of 84-B10 might be dependent on antagonizing ferroptosis. In accordance, lipid peroxide accumulation and downregulation of key ferroptosis suppressors were reversed using 84-B10 treatment both in vivo and in vitro. In addition, 84-B10 inhibited cisplatin-induced mitochondrial damage and mitochondrial reactive oxygen species (mtROS) production and restored superoxide dismutases (SODs). Furthermore, 84-B10 showed similar therapeutic effects to MnTBAP (a cell-permeable SOD mimetic) in eliminating mtROS, restoring mitochondrial homeostasis, and inhibiting ferroptosis under cisplatin challenge. Comparable effects of 84-B10 and liproxstatin-1 in ameliorating cisplatin-induced ferroptosis were observed. However, liproxstatin-1 failed to prevent mitochondrial dysfunction. These data indicated that mtROS might act upstream of cisplatin-induced tubular ferroptosis. Taken together, the novel 3-phenylglutaric acid derivative 84-B10 showed therapeutic potential against cisplatin-induced nephrotoxicity possibly by restoring mitochondria homeostasis and inhibiting mtROS-induced ferroptosis, which suggests the potential use of 84-B10 in preventing and treating cisplatin-nephrotoxicity.
顺铂是最有效的化疗药物之一，广泛用于癌症治疗。然而，其临床应用受到肾毒性的限制。新的研究结果表明，铁死亡和线粒体功能障碍均介导顺铂诱导的肾毒性。在本研究中，发现一种新型的3-苯基戊二酸衍生物5-[[2-(4-甲氧基苯氧基)-5-(三氟甲基)苯基]氨基]-5-氧代-3-苯基戊酸（简称84-B10）对顺铂诱导的急性肾损伤具有保护作用，且无促肿瘤作用。全基因组转录组分析表明，84-B10的保护作用可能依赖于拮抗铁死亡。相应地，在体内和体外使用84-B10处理均可逆转脂质过氧化物积累和关键铁死亡抑制因子的下调。此外，84-B10抑制顺铂诱导的线粒体损伤和线粒体活性氧（mtROS）生成，并恢复超氧化物歧化酶（SOD）。此外，在顺铂攻击下，84-B10在消除mtROS、恢复线粒体稳态和抑制铁死亡方面显示出与MnTBAP（一种细胞可渗透的SOD模拟物）相似的治疗效果。观察到84-B10和脂氧素A1在改善顺铂诱导的铁死亡方面具有可比的效果。然而，脂氧素A1未能预防线粒体功能障碍。这些数据表明，mtROS可能在顺铂诱导的肾小管铁死亡上游起作用。综上所述，新型3-苯基戊二酸衍生物84-B10可能通过恢复线粒体稳态和抑制mtROS诱导的铁死亡，对顺铂诱导的肾毒性具有治疗潜力，这表明84-B10在预防和治疗顺铂肾毒性方面具有潜在用途。
