Dataset Information

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

ABSTRACT: HIF-1? 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-1? 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-1? stabilization. Our study demonstrates an oxygen- and prolyl hydroxylase-independent regulation of HIF-1? 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-1? 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-1? 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.

SUBMITTER: Wilkes JG

PROVIDER: S-EPMC5959274 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Wilkes Justin G JG O'Leary Brianne R BR Du Juan J Klinger Adrienne R AR Sibenaller Zita A ZA Doskey Claire M CM Gibson-Corley Katherine N KN Alexander Matthew S MS Tsai Susan S Buettner Garry R GR Cullen Joseph J JJ

Clinical & experimental metastasis 20180202 1-2

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 tr ...[more]

PMID: 29396728

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Project description:Rationale: Ascorbate is an essential micronutrient known for redox functions at normal physiologic concentrations. In recent decades, pharmacological ascorbate has been found to selectively kill tumour cells. However, the dosing frequency of pharmacologic ascorbate in humans has not yet been defined. Methods: We determined that among five hepatic cell lines, Huh-7 cells were the most sensitive to ascorbate. The effects of high-dose ascorbate on hepatoma were therefore assessed using Huh-7 cells and xenograft tumour mouse model. Results: In Huh-7 cells, ascorbate induced a significant increase in the percentage of cells in the G0/G1 phase, apoptosis and intracellular levels of ROS. High doses of ascorbate (4.0 pmol cell-1), but not low doses of ascorbate (1.0 pmol cell-1), also served as a pro-drug that killed hepatoma cells by altering mitochondrial respiration. Furthermore, in a Huh-7 cell xenograft tumour mouse model, intraperitoneal injection of ascorbate (4.0 g/kg/3 days) but not a lower dose of ascorbate (2.0 g/kg/3 days) significantly inhibited tumour growth. Gene array analysis of HCC tumour tissue from xenograft mice given IP ascorbate (4.0 g/kg/3 days) identified changes in the transcript levels of 192 genes/ncRNAs involved in insulin receptor signalling, metabolism and mitochondrial respiration. Consistent with the array data, gene expression levels of AGER, DGKK, ASB2, TCP10L2, Lnc-ALCAM-3, and Lnc-TGFBR2-1 were increased 2.05-11.35 fold in HCC tumour tissue samples from mice treated with high-dose ascorbate, and IHC staining analysis also verified that AGER/RAGE and DGKK proteins were up-regulated, which implied that AGER/RAGE and DGKK activation might be related to oxidative stress, leading to hepatoma cell death. Conclusions: Our studies identified multiple mechanisms are responsible for the anti-tumour activity of ascorbate and suggest high doses of ascorbate with less frequency will act as a novel therapeutic agent for liver cancer in vivo.

Dataset Information

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

Publications

Pharmacologic ascorbate (P-AscH<sup>-</sup>) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma.

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