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 (H₂O₂), 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 H₂O₂, 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 H₂O₂ 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 H₂O₂. This multimodal approach has the potential to be an effective treatment for pancreatic ductal adenocarcinoma.