Vitamin C Sensitizes Melanoma to BET Inhibitors
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Abstract
Bromodomain and extraterminal inhibitors (BETi) are promising cancer therapies, yet prominent side effects of BETi at effective doses have been reported in phase I clinical trials. Here, we screened a panel of small molecules targeting epigenetic modulators against human metastatic melanoma cells. Cells were pretreated with or without ascorbate (vitamin C), which promotes DNA demethylation and subsequently changes the sensitivity to drugs. Top hits were structurally unrelated BETi, including JQ1, I-BET151, CPI-203, and BI-2536. Ascorbate enhanced the efficacy of BETi by decreasing acetylation of histone H4, but not H3, while exerting no effect on the expression of BRD proteins. Histone acetyltransferase 1 (HAT1), which catalyzes H4K5ac and H4K12ac, was downregulated by ascorbate mainly via the TET-mediated DNA hydroxymethylation pathway. Loss of H4ac, especially H4K5ac and H4K12ac, disrupted the interaction between BRD4 and H4 by which ascorbate and BETi blocked the binding of BRD4 to acetylated histones. Cotreatment with ascorbate and JQ1 induced apoptosis and inhibited proliferation of cultured melanoma cells. Ascorbate deficiency as modeled in Gulo−/− mice diminished the treatment outcome of JQ1 for melanoma tumorgraft. In contrast, ascorbate supplementation lowered the effective dose of JQ1 needed to successfully inhibit melanoma tumors in mice. On the basis of our findings, future clinical trials with BETi should consider ascorbate levels in patients. Furthermore, ascorbate supplementation might help reduce the severe side effects that arise from BETi therapy by reducing the dosage necessary for treatment. Significance: This study shows that ascorbate can enhance the efficacy of BET inhibitors, providing a possible clinical solution to challenges arising in phase I trials from the dose-dependent side effects of this class of epigenetic therapy. Cancer Res; 78(2); 572–83. ©2017 AACR.
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Giving ascorbate by injection may act synergistically with chemotherapy or radiotherapy.
“Numerous preclinical and clinical studies indicate that parenteral injection of pharmacological ascorbate does not interfere with chemotherapy or radiotherapy and may even act synergistically43,104,105.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [104]
Giving ascorbate by injection does not block the effects of chemotherapy or radiotherapy.
“Numerous preclinical and clinical studies indicate that parenteral injection of pharmacological ascorbate does not interfere with chemotherapy or radiotherapy and may even act synergistically43,104,105.”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [104]
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“Moreover, combined JQ1 plus vitamin C was previously reported to induce apoptosis in TNBC and melanoma cells [43,44].”
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“Previously, we reported that vitamin C sensitizes melanoma to BETi treatment [26].”
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“Other studies have also explored either ATRA 25,47,48 or ascorbate treatment as single-agent adjuvants in combination with other AML therapies 15,83,85 but never the two as a co-treatment or in the context of enhancing TET function.”
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- Authors
- Mustafi, S., Camarena, V., Volmar, C.-H., Huff, T. C., Sant, D. W., Brothers, S. P., Liu, Z.-J., Wahlestedt, C., & Wang, G.
- Affiliations
- University of Miami (US)
- 3Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
- ORCID
- Venue
- Cancer Research
- Published
- 2018-01-15
- Volume
- 78
- Issue
- 2
- Pages
- 572-583
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC5771981
- OpenAlex
- W2769459381
- Cited by
- 47
- References
- 41
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 6 · 2022: 2 · 2021: 12 · 2020: 11 · 2019: 10 · 2018: 2
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | NIH | National Cancer Institute (NCI) (R21CA191668)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (NINDS) (R01NS089525, R01NS092671)
- HHS | NIH | National Institute of Mental Health (NIMH) (R01MH110441)
- HHS | NIH | National Institute on Drug Abuse (NIDA) (R01DA035055)
- HHS | NIH | National Institute on Alcohol Abuse and Alcoholism (NIAA) (R01AA023781)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- vitamin C, BET inhibitors, melanoma, epigenetic therapy, histone acetylation, histone H4 acetylation, BRD4, DNA demethylation, JQ1, HAT1, combination therapy, ascorbate deficiency, adverse drug reactions
- MeSH terms
- Protein Domains, Bromodomain Containing Proteins, Acetylation, Animals, Antioxidants, Ascorbic Acid, Azepines, Drug Combinations, Drug Synergism, Histones, Humans, Melanoma, Mice, Inbred C57BL, Mice, Nude, Proteins, Triazoles, Tumor Cells, Cultured, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Apoptosis, Xenograft Model Antitumor Assays, Cell Proliferation, Mice
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