Enhanced Pharmacological Ascorbate Oxidation Radiosensitizes Pancreatic Cancer.

Pharmacologic ascorbate (P-AscH) is emerging as a promising adjuvant for advanced pancreatic cancer. P-AscH generates hydrogen peroxide (HO), leading to selective cancer cell cytotoxicity. Catalytic manganoporphyrins, such as MnT4MPyP, can increase the rate of oxidation of P-AscH, thereby increasing the flux of HO, resulting in increased cytotoxicity. We hypothesized that a multimodal treatment approach, utilizing a combination of P-AscH, ionizing radiation and MnT4MPyP, would result in significant flux of HO and pancreatic cancer cytotoxicity. P-AscH with MnT4MPyP increased the rate of oxidation of P-AscH and produced radiosensitization in all pancreatic cancer cell lines tested. Three-dimensional (3D) cell cultures demonstrated resistance to P-AscH, radiation or MnT4MPyP treatments alone; however, combined treatment with P-AscH and MnT4MPyP resulted in the inhibition of tumor growth, particularly when also combined with radiation. In vivo experiments using a murine model demonstrated an increased rate of ascorbate oxidation when combinations of P-AscH with MnT4MPyP were given, thus acting as a radiosensitizer. The translational potential was demonstrated by measuring increased ascorbate oxidation ex vivo, whereby MnT4MPyP was added exogenously to plasma samples from patients treated with P-AscH and radiation. Combination treatment utilizing P-AscH, manganoporphyrin and radiation results in significant cytotoxicity secondary to enhanced ascorbate oxidation and an increased flux of HO. This multimodal approach has the potential to be an effective treatment for pancreatic ductal adenocarcinoma.