Qi Chen, PhD

Associate Professor
Department of Pharmacology, Toxicology and Therapeutics
University of Kansas Medical Center, Kansas City, KS

image of Dr. Qi Chen

Abstract: High dose intravenous ascorbate (IVC) has attracted increasing interests as a low-toxic cancer therapy. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacologic concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. The selectivity is related to the mechanisms of action. We postulate that ascorbate-induced ROS have multiple mechanisms of action that preferably influence cancer cells. First, ascorbate-generated ROS induces DNA damage. Downstream to DNA damage, cellular NAD+ decreases as an effect of PARP activation. Decrease of NAD+ inhibited GAPDH activity and depletes ATP in cancer cells, while normal cells maintain their ATP levels. This phenomenon has a root in dysregulated glucose metabolism in cancer cells, known as the Warburg Effect, that cancer cells depend on a larger proportion on glycolysis for ATP whereas normal cells depend more on oxidative phosphorylation. Second, lack of NAD+ inhibits activity of Sirt-2, a tubulin deacetylase, and therefore increases tubulin acetylation, which in turn disrupts dynamics of microtubules. This influences cancer cells that are actively undergoing mitosis and migration. Third, when PARP is inhibited, excessive DNA damage results in cell death. Further, ascorbate inhibited EMT, an important process contributing to cancer metastasis. Finally, ascorbate enhanced collagen synthesis in tumor stroma. Despite the controversial reports on the effect of elevated collagen in tumor progression, the increased collagen by ascorbate treatment is associated with restriction of tumor invasion in our animal experiment and in patient.

Taken together, these data show multi-targeting effects of ascorbate that favor death/inhibition in cancer cells relative to normal cells. With minimal toxicity, the multi-targeting mechanism of ascorbate is advantageous because it could decrease the likelihood of resistance, and provides multiple opportunities for combining with standard chemo and radiation therapies.