Abstract 2995: Mechanisms of high dose ascorbate inhibiting pancreatic cancer growth and metastasis

Abstract Purpose: High-dose intravenous ascorbate (IVC) bypasses bioavailability barriers of oral ingestion and provides pharmacologic concentrations in tissues, and exhibits pro-oxidant anti-cancer activities. In pancreatic cancer pre-clinical models, ascorbate has been shown to sensitize the tumor to the 1st line chemotherapeutic drug gemcitabine. Here, we investigated the possible mechanisms of actions of ascorbate on pancreatic cancer growth and metastasis. Methods Orthotopic pancreatic cancer mouse model was utilized for evaluation of the effects of ascorbate in inhibiting tumor growth and metastasis. Molecular biological approaches were used in investigation the mechanisms of these effects. Results In the orthotopic mouse tumor model, ascorbate treatment alone decreased pancreatic cancer growth and metastasis. Ascorbate treatment enhanced expressions of epithelial markers and suppressed expression of mesenchymal markers in pancreatic cancer cells. MMP-2 expression and activity were decreased dose-dependently. Tumor tissues from ascorbate-treated mice had markedly increased collagen and desmoplasia in the extracellular matrix. Such fibrosis was not seen in normal tissues from the same mouse. In addition, ascorbate decreased the protein level of deacetylase HDAC6, and inhibited activity of the deacetylase Sirt-2 through depletion of NAD+. As a result, ascorbate robustly increased α-tubulin acetylation in pancreatic cancer cells. Acetylation promoted tubulin polymerization and stabilization, mimicking the cellular outcome of paclitaxel, resulted in inhibition of cell motility and mitosis. Conclusion Pharmacological concentrations of ascorbate affected pancreatic tumor cells and the tumor microenvironment, led to inhibition of tumor growth and metastasis. Citation Format: Qi Chen, Kishore Polireddy, Ruochen Dong, Ping Chen. Mechanisms of high dose ascorbate inhibiting pancreatic cancer growth and metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2995.