School of Public Health, Guangzhou Medical University, Guangzhou, Guangdong, 511436, China; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
Drug Resist Updat. 2018 Nov;41:1-25. doi: 10.1016/j.drup.2018.11.001. Epub 2018 Nov 14.
The successful treatment of cancer has significantly improved as a result of targeted therapy and immunotherapy. However, during chemotherapy, cancer cells evolve and can acquire "multidrug resistance" (MDR), which significantly limits the efficacy of cancer treatment and impacts patient survival and quality of life. Among the approaches to reverse MDR, modulating reactive oxidative species (ROS) may represent a strategy to kill MDR cancer cells that are mechanistically diverse. ROS in cancer cells play a central role in regulating and inducing apoptosis, thereby modulating cancer cells proliferation, survival and drug resistance. The levels of ROS and the activity of scavenging/anti-oxidant enzymes in drug resistant cancer cells are typically increased compared to non-MDR cancer and normal cells. Consequently, MDR cancer cells may be more susceptible to alterations in ROS levels. Numerous studies suggest that compounds modulating cellular ROS levels can enhance MDR cancer cell death and sensitize MDR cancer cells to certain chemotherapeutic drugs. In the current review, we discuss the critical and targetable redox-regulating enzymes, including mitochondrial electron transport chain (ETC) complexes, NADPH oxidases (NOXs), enzymes related to glutathione metabolism, glutamate/cystine antiporter xCT, thioredoxin reductases (TrxRs), nuclear factor erythroid 2-related factor 2 (Nrf2), and their roles in regulating cellular ROS levels, drug resistance as well as their clinical significance. We also discuss and summarize the findings in the past decade regarding the efficacy of ROS modulators for the treatment of MDR cancer alone or as sensitizing compounds. Compounds that are efficacious in modulating ROS generation represent a prominent class of drug candidates that warrants evaluation in clinical trials for patients harboring MDR cancers.
由于靶向治疗和免疫疗法的成功，癌症的治疗得到了显著改善。然而，在化疗过程中，癌细胞会发生进化，并可能获得“多药耐药性”（MDR），这极大地限制了癌症治疗的效果，并影响了患者的生存和生活质量。在逆转 MDR 的方法中，调节活性氧物种（ROS）可能是一种杀死机制多样的 MDR 癌细胞的策略。癌细胞中的 ROS 在调节和诱导细胞凋亡中起着核心作用，从而调节癌细胞的增殖、存活和耐药性。与非 MDR 癌症和正常细胞相比，耐药性癌细胞中的 ROS 水平和清除/抗氧化酶的活性通常会增加。因此，MDR 癌细胞可能更容易受到 ROS 水平变化的影响。许多研究表明，调节细胞 ROS 水平的化合物可以增强 MDR 癌细胞的死亡，并使 MDR 癌细胞对某些化疗药物敏感。在本综述中，我们讨论了关键的可靶向氧化还原调节酶，包括线粒体电子传递链（ETC）复合物、NADPH 氧化酶（NOXs）、与谷胱甘肽代谢相关的酶、谷氨酸/胱氨酸反向转运蛋白 xCT、硫氧还蛋白还原酶（TrxRs）、核因子红细胞 2 相关因子 2（Nrf2），以及它们在调节细胞 ROS 水平、耐药性以及它们的临床意义方面的作用。我们还讨论并总结了过去十年中关于 ROS 调节剂单独或作为增敏化合物治疗 MDR 癌症的疗效的发现。在调节 ROS 产生方面有效的化合物代表了一类突出的候选药物，值得在患有 MDR 癌症的患者中进行临床试验评估。
