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

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.

The superoxide dismutase mimetic GC4419 enhances tumor killing when combined with stereotactic ablative radiation

“…Overexpression of catalase, the primary but not only hydrogen peroxide detoxifying enzyme, effectively eliminated the enhanced radiation response when tumors were treated with radiation and GC4419. This finding is consistent with recent reports that suggest that elevated levels of hydrogen peroxide either produced by SOD mimetics, or by altering metabolic processes to produce more hydrogen peroxide, is an effective strategy in cancer therapy (48).…”

Superoxide Dismutases (SODs) and SOD Mimetics

“…This review is focused on understanding the spatiotemporal nature of MnSOD regulation in the context of a changing tumor microenvironment, which is necessary to improve the design of oxidant- or antioxidant-based therapeutic strategies for the treatment of cancer. In primary research articles by Chatterjee et al [ 8 ] and Heer et al [ 9 ], these investigators use SOD mimetics to enhance anti-cancer treatment. Chatterjee et al [ 8 ] demonstrate that SOD mimetics, in combination with radiation, inhibit prostate cancer growth while simultaneously protecting the normal prostate tissue from radiation damage.…”

“…Chatterjee et al [ 8 ] demonstrate that SOD mimetics, in combination with radiation, inhibit prostate cancer growth while simultaneously protecting the normal prostate tissue from radiation damage. Heer et al [ 9 ] enhance the anti-tumor effect of pharmacological ascorbate with the addition of SOD mimetics by enhancing hydrogen peroxide levels in the tumor.…”

Small Molecule Catalysts with Therapeutic Potential

“…Perhaps in part inspired by this kind of “almost but not quite natural” cytotoxic redox catalysis, compounds such as the manganese complex mangafodipir (2-[2-[carboxylatomethyl-[[5-[[hydroxy(oxido)phosphoryl]oxymethyl]-2-methyl-3-oxidopyridin-4-yl]methyl]amino]ethyl-[[2-methyl-3-oxido-5-(phosphonooxymethyl)pyridin-4-yl]methyl]amino] acetate; manganese(2+)) have been applied successfully by Batteux and his colleagues as radical generators in a range of target cells, including human leukocytes and murine CT26 colon cancer cells [ 77 , 78 ]. Similar studies have confirmed these findings, employing, for instance, the superoxide dismutase mimic GC4419 to transfer one electron from ascorbate to O 2 •− , thereby subsequently generating the more aggressive H 2 O 2 and distorting the intracellular redox balance [ 79 ]. Ironically, other SOD mimetics, such as MnDPDP and calmangafodipin [Ca 4 Mn(DPDP) 5 ] have been described as selective cyto-protective agents, in essence acting via an antioxidant mechanism [ 80 ].…”