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02.02.2018 | Research Paper

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

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

Erschienen in: Clinical & Experimental Metastasis | Ausgabe 1-2/2018

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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.

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Titel: Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma
verfasst von: Justin G. Wilkes
Brianne R. O’Leary
Juan Du
Adrienne R. Klinger
Zita A. Sibenaller
Claire M. Doskey
Katherine N. Gibson-Corley
Matthew S. Alexander
Susan Tsai
Garry R. Buettner
Joseph J. Cullen
Publikationsdatum: 02.02.2018
Verlag: Springer Netherlands
Erschienen in: Clinical & Experimental Metastasis / Ausgabe 1-2/2018
Print ISSN: 0262-0898
Elektronische ISSN: 1573-7276
DOI: https://doi.org/10.1007/s10585-018-9876-z

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

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