Penta-azamacrocyclic SOD Mimetics Enhance Pharmacological Ascorbate Oxidation and Anticancer effects in an H 2 O 2 -dependent Manner

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 H 2 O 2 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 H 2 O 2 , 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.