title: Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis.
abstract: Cancer cell resistance to chemotherapy is still a heavy burden that impairs the response of many cancer patients to conventional chemotherapy. Using drug combinations is one therapeutic approach to overcome the developing resistance to any one drug. Oxidative stress is now a generally regarded hallmark of cancer that can be one approach to selectively target cancer cells while sparing normal cells. With the aim of increasing oxidative stress in cancer cells to a lethal set point, we have generated and combined several series of redox active compounds that act at different points of the cellular oxidative cascade. The premise of such combinations is to deplete of endogenous antioxidant defence proteins (e.g., Glutathione) while concomitantly increasing the generation of ROS via metal redox recycling and Fenton chemistry which eventually leads to the disruption of cellular redox homeostasis and induction of cell death. Through this approach, we have identified highly synergistic combinations of two distinctive classes of compounds (Azines and Copper(II) complexes of 2-pyridyl ketone thiosemicarbazones) which are capable of eliminating cancer cells without concomitant increase in toxicity toward normal cells. In one of our most potent combinations, a combination index (CI) value of 0.056 was observed, representing a 17 fold enhancement in activity beyond additive effects. Such new combination regimen of redox active compounds can be one step closer to potentially safer low dose chemotherapy.
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, NSW 2800, Australia.
authors.forename: Fady N
authors.initials: FN
authors.lastname: Akladios
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, NSW 2800, Australia.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Andrew
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, NSW 2800, Australia. Electronic address: cparkinson@csu.edu.au.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Parkinson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D003300:Copper / Q000737:chemistry; D004338:Drug Combinations; D004357:Drug Synergism; D005415:Flavins / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000819:agonists* / Q000378:metabolism; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004338:Drug Combinations; D005415:Flavins; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; D003300:Copper; D005978:Glutathione
keywords: Copper complex; Flavin analogue; Metal chelator; Oxidative stress; Synergistic combinations