Superoxide Dismutase Mimetic GC4419 Enhances the Oxidation of Pharmacological Ascorbate and Its Anticancer Effects in an H(2)O(2)-Dependent Manner

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 H(2)O(2). 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(−)/O(2)(•−) oxidoreductase as evidenced by the increased rate of oxygen consumption, steady-state concentrations of ascorbate radical, and H(2)O(2) 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 H(2)O(2), 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.