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.