Experimental therapeutics: targeting the redox Achilles heel of cancer.
Reactive oxygen species (ROS) have recently emerged as promising targets for anticancer drug discovery. Constitutively elevated levels of cellular oxidative stress and dependence on mitogenic and anti-apoptotic ROS signaling represent a specific vulnerability of malignant cells that can be selectively targeted by novel pro- and antioxidant redox chemotherapeutics. This review discusses small-molecule anticancer redox drugs currently in various phases of preclinical and clinical development that are characterized by their unique mechanism of action, including small-molecule superoxide dismutase and catalase mimetics, bioreductively activated pro-oxidant redox catalysts, metal-based pro-oxidants, hypoxia-selective free radical precursors, and specific antagonists of the cancer cell antioxidant glutathione or thioredoxin redox systems. Based on ongoing redox biomarker discovery and validation, future redox phenotyping and genotyping may guide the selection of novel redox chemotherapeutics that efficiently target the redox Achilles heel of the individual tumor.
University of Arizona, Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85721, USA.
Christopher M
CM
Cabello
Warner B
WB
Bair
Georg T
GT
Wondrak
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism*; D005240:Feasibility Studies; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D000975:Antioxidants; D017382:Reactive Oxygen Species