119 - Penta-azamacrocyclic SOD Mimetics Enhance Pharmacological Ascorbate Oxidation and Anticancer effects in an H2O2-dependent Manner

Abstract

Lung cancer accounts for approximately one-fourth of cancer deaths worldwide; new therapeutic approaches are desperately needed. An emerging adjuvant therapy currently in clinical trials is pharmacological ascorbate (P-AscH‒). The anti-cancer effects of P-AscH‒ are a result of its oxidation, resulting in increased flux and steady-state levels of H2O2 in tumors. P-AscH‒ oxidation can be catalyzed by transition metal ions. P-AscH‒ has been shown to reduce Mn(III)-porphyrin superoxide dismutase (SOD) mimetics, increasing the rate of P-AscH‒ oxidation and enhancing the anti-tumor effect of P-AscH‒. However, the ability of Mn(II)-containing SOD mimetics to enhance the anticancer effects of P-AscH‒ is unknown. The current study shows that Mn(II)-containing penta-azamacrocylic SOD mimetics GC4419 and GC4401 can enhance P-AscH‒ oxidation, as determined by increased oxygen consumption and steady-state concentrations of ascorbate radical in complete cell culture media. These mimetics also enhance the toxicity of P-AscH‒ in H292 and H1299 lung cancer cell lines. This enhanced P-AscH‒-induced lung cancer cell killing was shown to be dependent on the catalytic activity of the SOD mimics and the subsequent generation of H2O2, as determined using conditional overexpression of catalase in H1299 cells. GC4419 combined with P-AscH‒ was also capable of enhancing radiation-induced cancer cell killing in a manner that appears to be greater-than-additive. Since P-AscH‒ and GC4419 are both being tested in individual phase II cancer clinical trials in combination with radiation therapy, these results support the proposal that the combination of GC4419 and P-AscH‒ may provide an effective means by which to significantly enhance radiation responses.