活性氧在肿瘤顺铂耐药中的作用研究进展

Research progress in roles of reactive oxygen species in cisplatin resistance of tumor

顺铂是目前应用最广泛的抗癌药物之一。作为DNA络合物,顺铂不仅能够通过结合并损伤细胞核DNA,诱导DNA损伤应答,而且能够通过结合线粒体DNA,诱导线粒体功能紊乱,活性氧(ROS)过度产生,最终导致细胞凋亡坏死。ROS是一类化学性质活泼的氧分子衍生物的统称,主要由细胞内线粒体以及NADPH过氧化物酶产生。过量的ROS能够导致核酸、脂质以及蛋白质发生氧化损伤,是顺铂抗肿瘤效应的重要介质。然而,在肿瘤顺铂耐药的进程中,ROS亦发挥了重要作用。因此,本文综述了顺铂耐药肿瘤中ROS的代谢特点和ROS调控顺铂耐药的多种机制,包括上调顺铂转运体表达、增强细胞DNA损伤修复能力、提高核转录因子红系2相关因子2、低氧诱导因子-1α的蛋白水平和转录活性以及调控线粒体动态活动等方面。最后,本文还总结了ROS诱导剂和抗氧化系统抑制剂这两类ROS调节药物的相关研究,希望为提高顺铂疗效,克服肿瘤顺铂耐药提供治疗新思路。

Cisplatin is widely applied in clinical practice for the treatment of various solid malignancies. Mechanistically, cisplatin can bind to nuclear and mitochondrial DNA and induce DNA damage response, mitochondrial dysfunction as well as excessive production of reactive oxygen species(ROS),leading to apoptosis and necrosis of tumor. ROS, which are mainly produced by mitochondria and NADPH oxidases(NOXs), are defined as unstable molecules that contain oxygen. Excessive ROS can cause oxidative damage to nucleic acids, lipids and proteins, suggesting its indispensable role in the antitumor effect of cisplatin. However, ROS also play an important role in the process of cisplatin resistance of tumor. Therefore, this article reviews the metabolic properties of ROS in cisplatin-resistant tumors and clarify mechanisms through which ROS may regulate cisplatin resistance. Various mechanisms including up-regulation of cisplatin transporters, enhanced cellular capability to repair DNA damage,increased protein expression and transcriptional activity of Nrf2 and HIF-1α as well as mitochondrial dynamics are discussed here. Finally, ROS inducers and antioxidant system inhibitors which could target intracellular ROS are summarized to provide new ideas about how to improve therapeutic effects of cisplatin and overcome chemoresistance.