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Lung cancer, together with head and neck cancer, accounts for more than one-fourth of cancer deaths worldwide. New, non-toxic therapeutic approaches are needed. High-dose IV vitamin C (aka, pharmacological ascorbate; P-AscH) represents a promising adjuvant to radiochemotherapy that exerts its anti-cancer effects via metal-catalyzed oxidation to form H2O2. Mn(III)-porphyrins possessing superoxide dismutase (SOD) mimetic activity have been shown to increase the rate of oxidation of AscH, enhancing the anti-tumor effects of AscH in several cancer types. The current study demonstrates that the Mn(II)-containing pentaazamacrocyclic selective SOD mimetic GC4419 may serve as an AscH/O2•− oxidoreductase as evidenced by the increased rate of oxygen consumption, steady-state concentrations of ascorbate radical, and H2O2 production in complete cell culture media. GC4419, but not CuZnSOD, was shown to significantly enhance the toxicity of AscH in H1299, SCC25, SQ20B, and Cal27 cancer cell lines. This enhanced cancer cell killing was dependent upon the catalytic activity of the SOD mimetic and the generation of H2O2, as determined using conditional overexpression of catalase in H1299T cells. GC4419 combined with AscH was also capable of enhancing radiation-induced cancer cell killing. Currently, AscH and GC4419 are each being tested separately in clinical trials in combination with radiation therapy. Data presented here support the hypothesis that the combination of GC4419 and AscH may provide an effective means by which to further enhance radiation therapy responses


OAfund, SOD mimetic, pharmacological ascorbate, vitamin C, head and neck cancer, lung cancer, radiation therapy, GC4419, oxidative stress, hydrogen peroxide


The authors would like to thank the Radiation and Free Radical Research Core in the Holden Comprehensive Cancer Center. This work was supported by Galera Therapeutics Inc., as well as NIH grants T32 CA078586, T32 DC000040, R01CA182804, R01CA169046, P30CA086862, T35HL007485-34, F30 CA213817, 5T32 GM007337 and the Carver Research Program of Excellence in Redox Biology and Medicine and the Carver College of Medicine Medical Student Summer Research Program. The authors would also like to thank Gareth Smith for assistance in preparing the manuscript.

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Antioxidants 2018, 7, 18.


© 2018 by the authors

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