High Concentrations of L-Ascorbic Acid Specifically Inhibit the Growth of Human Leukemic Cells via Downregulation of HIF-1α Transcription
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We examined the antileukemic effects of high concentrations of L-ascorbic acid (high AA) on human leukemic cells. In vitro, high AA markedly induced apoptosis in various leukemic cell lines by generating hydrogen peroxide (H2O2) but not in normal hematopoietic stem/progenitor cells. High AA significantly repressed leukemic cell proliferation as well as neoangiogenesis in immunodeficient mice. We then noted that in leukemic cells, HIF-1α transcription was strongly suppressed by high AA and correlated with the transcription of VEGF. Our data indicate that exposure to high AA markedly increased the intracellular AA content of leukemic cells and inhibited the nuclear translocation of NF-κB, which mediates expression of HIF-1α. We next generated K562 cells that overexpressed HIF-1α (K562-HIF1α cells) and assessed the mechanistic relationship between inhibition of HIF-1α transcription and the antileukemic effect of high AA. The ability of high AA to induce apoptosis was significantly lower in K562-HIF1α cells than in K562 cells in vitro. We found that expression of HIF-1α-regulated antiapoptotic proteins of the Bcl-2 family, such as Mcl-1, Bcl-xL, and Bcl-2, was significantly suppressed by high AA in K562 cells, but was sustained at higher levels in K562-HIF1α cells, regardless of high AA exposure. Moreover, repression of cell proliferation and neoangiogenesis by high AA was completely abrogated in mice receiving transplants of K562-HIF1α cells. These results indicate that, along with H2O2 generation, downregulation of HIF-1α transcription plays a crucial role in growth inhibition of human leukemic cells by high AA.
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Native vitamin C is toxic in culture through the formation of extracellular H2O2, potentially masking its more biologically relevant epigenetic effects.
“Multiple lines of evidence have suggested that vitamin C, in its native form, is toxic in culture through the formation of extracellular H2O2(refs 16, 17) potentially masking its more biologically relevant epigenetic effects.”
From Vitamin C-induced epigenomic remodelling in IDH1 mutant acute myeloid leukaemia (2018) · cites this paper as [17]
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- Authors
- Kawada, H., Kaneko, M., Sawanobori, M., Uno, T., Matsuzawa, H., Nakamura, Y., Matsushita, H., & Ando, K.
- Affiliations
- Tokai University (JP)
- Corresponding author
- Kawada, Hiroshi
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-04-23
- Volume
- 8
- Issue
- 4
- Pages
- e62717
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3633866
- OpenAlex
- W1988027547
- Cited by
- 55
- References
- 63
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 3 · 2022: 10 · 2021: 7 · 2020: 2 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 1 · 2015: 9 · 2014: 2 · 2013: 1
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- 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 › Pharmacology › Flavonoids in Medical Research
- Keywords
- vitamin C, high-dose vitamin C, leukemia, apoptosis, hydrogen peroxide, NF-κB nuclear translocation, vascular endothelial growth factor, neoangiogenesis, Bcl-2 family proteins, Mcl-1, Bcl-xL, Bcl-2, K562 cells, antileukemic effect
- MeSH terms
- Animals, Antineoplastic Agents, Ascorbic Acid, Disease Models, Animal, Hematopoietic Stem Cells, Humans, Leukemia, Transcription, Genetic, Gene Expression Regulation, Leukemic, Disease Progression, K562 Cells, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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