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Antioxidants 2018, 7(1), 18; https://doi.org/10.3390/antiox7010018

Superoxide Dismutase Mimetic GC4419 Enhances the Oxidation of Pharmacological Ascorbate and Its Anticancer Effects in an H2O2-Dependent Manner

1
Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa College of Medicine, Iowa City, IA 52242, USA
2
Galera Therapeutics, Malvern, PA 19355, USA
*
Authors to whom correspondence should be addressed.
Received: 2 November 2017 / Revised: 12 January 2018 / Accepted: 16 January 2018 / Published: 19 January 2018
(This article belongs to the Special Issue Superoxide Dismutase (SOD) Enzymes, Mimetics and Oxygen Radicals)
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Abstract

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. View Full-Text
Keywords: SOD mimetic; pharmacological ascorbate; vitamin C; head and neck cancer; lung cancer; radiation therapy; GC4419; oxidative stress; hydrogen peroxide SOD mimetic; pharmacological ascorbate; vitamin C; head and neck cancer; lung cancer; radiation therapy; GC4419; oxidative stress; hydrogen peroxide
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Heer, C.D.; Davis, A.B.; Riffe, D.B.; Wagner, B.A.; Falls, K.C.; Allen, B.G.; Buettner, G.R.; Beardsley, R.A.; Riley, D.P.; Spitz, D.R. Superoxide Dismutase Mimetic GC4419 Enhances the Oxidation of Pharmacological Ascorbate and Its Anticancer Effects in an H2O2-Dependent Manner. Antioxidants 2018, 7, 18.

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