Pharmacologic ascorbate treatment (P-AscH-, high-dose, intravenous
vitamin C) results in a transient short-term increase in the flux of
hydrogen peroxide that is preferentially cytotoxic to
cancer cells versus normal cells. This study examines whether an increase in
hydrogen peroxide is sustained posttreatment and potential mechanisms involved in this process. Cellular bioenergetic profiling following treatment with P-AscH- was examined in tumorigenic and nontumorigenic cells. P-AscH- resulted in sustained increases in the rate of cellular oxygen consumption (OCR) and
reactive oxygen species (ROS) in
tumor cells, with no changes in nontumorigenic cells. Sources for this increase in ROS and OCR were DUOX 1 and 2, which are silenced in pancreatic ductal
adenocarcinoma, but upregulated with P-AscH- treatment. An inducible
catalase system, to test causality for the role of
hydrogen peroxide, reversed the P-AscH--induced increases in DUOX, whereas DUOX inhibition partially rescued P-AscH--induced toxicity. In addition, DUOX was significantly downregulated in
pancreatic cancer specimens compared with normal pancreas tissues. Together, these results suggest that P-AscH--induced toxicity may be enhanced by late metabolic shifts in
tumor cells, resulting in a feed-forward mechanism for generation of
hydrogen peroxide and induction of metabolic stress through enhanced DUOX expression and rate of oxygen consumption. SIGNIFICANCE: A high dose of
vitamin C, in addition to delivering an acute exposure of H2O2 to
tumor cells, activates DUOX in
pancreatic cancer cells, which provide sustained production of H2O2.