Faculty Collaboration Database

Pharmacologic ascorbate (P-AscH^-) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma. Clin Exp Metastasis 2018 Feb;35(1-2):37-51

Date

02/06/2018

Pubmed ID

29396728

Pubmed Central ID

PMC5959274

DOI

10.1007/s10585-018-9876-z

Scopus ID

2-s2.0-85045038767 (requires institutional sign-in at Scopus site)   31 Citations

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.

Author List

Wilkes JG, O'Leary BR, Du J, Klinger AR, Sibenaller ZA, Doskey CM, Gibson-Corley KN, Alexander MS, Tsai S, Buettner GR, Cullen JJ

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Animals
Ascorbic Acid
Cell Hypoxia
Cell Line, Tumor
Cell Proliferation
Cell Survival
Disease Progression
Dose-Response Relationship, Drug
Humans
Hydrogen Peroxide
Hypoxia-Inducible Factor 1, alpha Subunit
Mice
Mice, Nude
Neoplasm Metastasis
Pancreatic Neoplasms
Prolyl Hydroxylases
Protein Processing, Post-Translational
Vascular Endothelial Growth Factor A