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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma.

Authors: Wilkes, Justin G; O'Leary, Brianne R; Du, Juan; Klinger, Adrienne R; Sibenaller, Zita A; Doskey, Claire M; Gibson-Corley, Katherine N; Alexander, Matthew S; Tsai, Susan; Buettner, Garry R; Cullen, Joseph J

Published In Clin Exp Metastasis, (2018 Feb)

Abstract: HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH-), induces cytotoxicity and oxidative stress selectively in cancer cells by acting as a pro-drug for the delivery of hydrogen peroxide (H2O2); early clinical data suggest improved survival and inhibition of metastasis in patients being actively treated with P-AscH-. Previous studies have demonstrated that activation of HIF-1α is necessary for P-AscH- sensitivity. We hypothesized that pancreatic cancer (PDAC) progression and metastasis could be be targeted by P-AscH- via H2O2-mediated inhibition of HIF-1α stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1α by P-AscH-. Additionally, P-AscH- decreased VEGF secretion in a dose-dependent manner that was reversible with catalase, consistent with an H2O2-mediated mechanism. Pharmacological and genetic manipulations of HIF-1α did not alter P-AscH--induced cytotoxicity. In vivo, P-AscH- inhibited tumor growth and VEGF expression. We conclude that P-AscH- suppresses the levels of HIF-1α protein in hypoxic conditions through a post-translational mechanism. These findings suggest potential new therapies specifically designed to inhibit the mechanisms that drive metastases as a part of PDAC treatment.

PubMed ID: 29396728 Exiting the NIEHS site

MeSH Terms: Adenocarcinoma/blood supply; Adenocarcinoma/metabolism*; Adenocarcinoma/pathology; Animals; Ascorbic Acid/administration & dosage; Ascorbic Acid/pharmacology*; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation/drug effects; Cell Survival/drug effects; Disease Progression; Dose-Response Relationship, Drug; Humans; Hydrogen Peroxide/metabolism; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors*; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Mice; Mice, Nude; Neoplasm Metastasis; Pancreatic Neoplasms/blood supply; Pancreatic Neoplasms/metabolism*; Pancreatic Neoplasms/pathology; Prolyl Hydroxylases/metabolism; Protein Processing, Post-Translational/drug effects; Vascular Endothelial Growth Factor A/metabolism

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