| Summary: | Pancreatic cancer cells (PDACs) are more susceptible to an oxidative insult than normal cells, resulting in greater cytotoxicity upon exposure to agents that increase pro-oxidant levels. Pharmacological ascorbate (P-AscH<sup>−</sup>), i.e., large amounts given intravenously (IV), generates significant fluxes of hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), resulting in the killing of PDACs but not normal cells. Recent studies have demonstrated that P-AscH<sup>−</sup> radio-sensitizes PDAC but is a radioprotector to normal cells and tissues. Several mechanisms have been hypothesized to explain the dual roles of P-AscH<sup>−</sup> in radiation-induced toxicity including the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2), RelB, as well as changes in bioenergetic profiles. We have found that P-AscH<sup>−</sup> in conjunction with radiation increases Nrf2 in both cancer cells and normal cells. Although P-AscH<sup>−</sup> with radiation decreases RelB in cancer cells vs. normal cells, the knockout of RelB does not radio-sensitize PDACs. Cellular bioenergetic profiles demonstrate that P-AscH<sup>−</sup> with radiation increases the ATP demand/production rate (glycolytic and oxidative phosphorylation) in both PDACs and normal cells. Knocking out catalase results in P-AscH<sup>−</sup> radio-sensitization in PDACs. In a phase I trial where P-AscH<sup>−</sup> was included as an adjuvant to the standard of care, short-term survivors had higher catalase levels in tumor tissue, compared to long-term survivors. These data suggest that P-AscH<sup>−</sup> radio-sensitizes PDACs through increased peroxide flux. Catalase levels could be a possible indicator for how tumors will respond to P-AscH<sup>−</sup>.
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