Pharmacologic ascorbate (P-AscH−) suppresses hypoxia-inducible Factor-1α (HIF-1α) in pancreatic adenocarcinoma
Open accessAbstract
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 (H 2 O 2); 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 H 2 O 2-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 H 2 O 2-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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Evidence is increasing that ascorbate can inhibit tumours dependent on HIF1α.
“there is growing evidence that HIF1α-dependent tumour growth may be inhibited by ascorbate78,79.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [78]
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References 55 · Cited by 36
- Authors
- Wilkes, J. G., O’Leary, B. R., Du, J., Klinger, A. R., Sibenaller, Z. A., Doskey, C. M., Gibson-Corley, K. N., Alexander, M. S., Tsai, S., Buettner, G. R., & Cullen, J. J.
- Affiliations
- University of Iowa (US)
- Medical College of Wisconsin (US)
- Corresponding author
- Cullen, Joseph J.
- ORCID
- Venue
- Clinical & Experimental Metastasis
- Published
- 2018-02
- Volume
- 35
- Issue
- 1-2
- Pages
- 37-51
- ISSN
- 0262-0898 (ISSN-L)
- 1573-7276
- PMC
- PMC5959274
- OpenAlex
- W2786868231
- Cited by
- 36
- References
- 55
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 3 · 2021: 9 · 2020: 5 · 2019: 2 · 2018: 2
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical & Experimental Metastasis (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institutes of Health (CA18451, CA148062, CA169046, CA086862)
- U.S. Department of Veterans Affairs (1I01BX001318-01A2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Keywords
- pharmacological ascorbate, vitamin C, HIF-1α, pancreatic ductal adenocarcinoma, hydrogen peroxide, vascular endothelial growth factor, metastasis, hypoxia, post-translational regulation, catalase, tumor growth inhibition, oxidative stress
- MeSH terms
- Adenocarcinoma, Animals, Ascorbic Acid, Cell Survival, Dose-Response Relationship, Drug, Humans, Hydrogen Peroxide, Mice, Nude, Neoplasm Metastasis, Pancreatic Neoplasms, Protein Processing, Post-Translational, Cell Hypoxia, Disease Progression, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Prolyl Hydroxylases
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