Pharmacological ascorbate enhances oxygen consumption and epigenetic reprogramming in pancreatic cancer

Administration of high doses of intravenous vitamin C is suggested to be an effective addition to chemotherapy and radiation for the treatment of pancreatic cancer. It is believed that vitamin C works by reacting with iron to produce high levels of hydrogen peroxide in the space surrounding tumors. This research focuses on how peroxide produced from vitamin C treatment can result in sustained changes to cancer cells to increase the toxicity of ascorbate through a surface protein, Dual Oxidase (DUOX). We believe that this DUOX protein produces additional peroxide and contributes to the toxicity of vitamin C by changing cellular metabolism and gene expression. We discovered that vitamin C treatment causes a sustained, long-term increase DUOX expression, reactive oxygen species generation, and metabolic changes. We observe that removal of the peroxide produced by Vitamin C prevents the increase in DUOX expression and reverses cancer cell killing. These results suggest that the peroxide from vitamin C is a mediator of increased DUOX expression. We also observed that nutritional levels of vitamin C are not able to increase DUOX expression. These studies also found that this protein’s expression is lost in pancreatic cancer cells in both our model systems and in patients. Patient loss of this protein expression is correlated with a decrease in survival. This research boosts our understanding how high doses of vitamin C lead to toxicity to cancer cells at high levels and how restoration of DUOX proteins by this treatment contributes to enhanced treatment outcomes.