Dharmaraja Allimuthu T
Department of Genetics and Genome Sciences and Comprehensive Cancer Center, School of Medicine, Case Western Reserve University , Cleveland, Ohio 44106, United States.
J Med Chem. 2017 Apr 27;60(8):3221-3240. doi: 10.1021/acs.jmedchem.6b01243. Epub 2017 Feb 14.
Evading persistent drug resistance in cancer and bacteria is quintessential to restore health in humans, and impels intervention strategies. A distinct property of the cancer phenotype is enhanced glucose metabolism and oxidative stress. Reactive oxygen species (ROS) are metabolic byproducts of aerobic respiration and are responsible for maintaining redox homeostasis in cells. Redox balance and oxidative stress are orchestrated by antioxidant enzymes, reduced thiols and NADP(H) cofactors, which is critical for cancer cells survival and progression. Similarly, Escherichia coli (E. coli) and life-threatening infectious pathogens such as Staphylococcus aureus (SA) and Mycobacterium tuberculosis (Mtb) are appreciably sensitive to changes in the intracellular oxidative environment. Thus, small molecules that modulate antioxidant levels and/or enhance intracellular ROS could disturb the cellular oxidative environment and induce cell death, and hence could serve as novel therapeutics. Presented here are a collection of approaches that involve ROS modulation in cells as a strategy to target cancer and bacteria.
在癌症和细菌中规避持续的耐药性对于恢复人类健康至关重要,并推动了干预策略的发展。癌症表型的一个显著特性是葡萄糖代谢增强和氧化应激。活性氧(ROS)是有氧呼吸的代谢副产物,负责维持细胞内的氧化还原稳态。氧化还原平衡和氧化应激由抗氧化酶、还原型硫醇和NADP(H)辅因子协调,这对癌细胞的存活和进展至关重要。同样,大肠杆菌(E. coli)以及诸如金黄色葡萄球菌(SA)和结核分枝杆菌(Mtb)等危及生命的传染性病原体对细胞内氧化环境的变化相当敏感。因此,调节抗氧化剂水平和/或增强细胞内ROS的小分子可能会扰乱细胞氧化环境并诱导细胞死亡,从而可作为新型治疗药物。本文介绍了一系列将细胞内ROS调节作为靶向癌症和细菌策略的方法。