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.

靶向治疗和免疫治疗的结果，癌症的成功治疗已得到显着改善。但是，在化疗过程中，癌细胞会进化并获得“多药耐药性”（MDR），这大大限制了癌症治疗的效力，并影响了患者的生存和生活质量。在逆转MDR的方法中，调节反应性氧化物质（ROS）可能代表杀死机制多样的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癌细胞和正常细胞相比，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。所以，MDR癌细胞可能更容易受到ROS水平变化的影响。大量研究表明，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。

在当前的审查中，我们讨论关键和针对性的氧化还原调节酶，包括线粒体电子运输链（ETC）复合物，NADPH氧化酶（NOX），与谷胱甘肽代谢有关的酶，谷氨酸/胱氨酸反转运蛋白xCT，硫氧还蛋白还原酶（TrxRs），核因子红系2相关因子2（Nrf2）及其在调节细胞ROS水平，耐药性中的作用及其临床意义。我们还讨论并总结了过去十年中有关ROS调节剂单独治疗MDR癌症或作为敏化化合物的功效的发现。能有效调节ROS生成的化合物代表了一类重要的候选药物，值得在临床试验中对具有MDR癌症的患者进行评估。