Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
Asu Vanda Gene Research Company, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Science Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
Pharmacol Res. 2021 May;167:105575. doi: 10.1016/j.phrs.2021.105575. Epub 2021 Mar 24.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor and its induction is of significant importance for protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) stimulate Nrf2 signaling, enhancing the activity of antioxidant enzymes such as catalase, superoxide dismutase and glutathione peroxidase. These enzymes are associated with retarding oxidative stress. On the other hand, Nrf2 activation in cancer cells is responsible for the development of chemoresistance due to disrupting oxidative mediated-cell death by reducing ROS levels. Cisplatin (CP), cis-diamminedichloroplatinum(II), is a potent anti-tumor agent extensively used in cancer therapy, but its frequent application leads to the development of chemoresistance as well. In the present study, association of Nrf2 signaling with chemoresistance to CP and protection against its deleterious effects is discussed. Anti-tumor compounds, mainly phytochemicals, retard chemoresistance by suppressing Nrf2 signaling. Upstream mediators such as microRNAs can regulate Nrf2 expression during CP chemotherapy regimens. Protection against side effects of CP is mediated via activating Nrf2 signaling and its downstream targets activating antioxidant defense system. Protective agents that activate Nrf2 signaling, can ameliorate CP-mediated ototoxicity, nephrotoxicity and neurotoxicity. Reducing ROS levels and preventing cell death are the most important factors involved in alleviating CP toxicity upon Nrf2 activation. As pre-clinical experiments advocate the role of Nrf2 in chemoprotection and CP resistance, translating these findings to the clinic can provide a significant progress in treatment of cancer patients.
核因子红细胞 2 相关因子 2（Nrf2）是一种重要的转录因子，其诱导对于防止氧化损伤具有重要意义。活性氧（ROS）水平的增加会刺激 Nrf2 信号通路，增强抗氧化酶如过氧化氢酶、超氧化物歧化酶和谷胱甘肽过氧化物酶的活性。这些酶与延缓氧化应激有关。另一方面，癌细胞中 Nrf2 的激活会导致化疗耐药的发生，因为它通过降低 ROS 水平来破坏氧化介导的细胞死亡。顺铂（CP），顺式二氨二氯铂（II），是一种广泛用于癌症治疗的有效抗肿瘤药物，但由于频繁应用，也会导致耐药性的产生。本研究探讨了 Nrf2 信号通路与 CP 化疗耐药性的关系以及对其有害作用的保护。抗肿瘤化合物，主要是植物化学物质，通过抑制 Nrf2 信号通路来延缓化疗耐药性。微 RNA 等上游介质可在 CP 化疗方案中调节 Nrf2 的表达。通过激活 Nrf2 信号通路及其下游靶标激活抗氧化防御系统来介导对 CP 副作用的保护。激活 Nrf2 信号通路的保护剂可改善 CP 引起的耳毒性、肾毒性和神经毒性。降低 ROS 水平和防止细胞死亡是缓解 Nrf2 激活后 CP 毒性的最重要因素。由于临床前实验证明了 Nrf2 在化学保护和 CP 耐药性中的作用，将这些发现转化为临床应用可以为癌症患者的治疗提供重大进展。
