Mebendazole Treatment Disrupts the Transcriptional Activity of Hypoxia-Inducible Factors 1 and 2 in Breast Cancer Cells
Open accessAbstract
Breast cancer is the most diagnosed cancer in women in the world. Mebendazole (MBZ) has been demonstrated to have preclinical efficacy across multiple cancers, including glioblastoma multiforme, medulloblastoma, colon, breast, pancreatic, and thyroid cancers. MBZ was also well tolerated in a recent phase I clinical trial of adults diagnosed with glioma. The mechanisms of action reported so far for MBZ include tubulin disruption, inhibiting angiogenesis, promoting apoptosis, and maintaining stemness. To elucidate additional mechanisms of action for mebendazole (MBZ), we performed RNA sequencing of three different breast cancer cell lines treated with either MBZ or vehicle control. We compared the top genes downregulated upon MBZ treatment with expression profiles of cells treated with over 15,000 perturbagens using the clue.io online analysis tool. In addition to tubulin inhibitors, the gene expression profile that correlated most with MBZ treatment matched the profile of cells treated with known hypoxia-inducible factor (HIF-1α and -2α) inhibitors. The HIF pathway is the main driver of the cellular response to hypoxia, which occurs in solid tumors. Preclinical data support using HIF inhibitors in combination with standard of care to treat solid tumors. Therefore, we tested the hypothesis that MBZ could inhibit the hypoxia response. Using RNA sequencing and HIF-reporter assays, we demonstrate that MBZ inhibits the transcriptional activity of HIFs in breast cancer cell lines and in mouse models of breast cancer by preventing the induction of HIF-1α, HIF-2α, and HIF-1β protein under hypoxia. Taken together, our results suggest that MBZ treatment has additional therapeutic efficacy in the setting of hypoxia and warrants further consideration as a cancer therapy.
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Mebendazole reduces HIF-1α, HIF-2α, and HIF-1β protein levels independently of transcript abundance.
“mebendazole (MBZ), an FDA-approved antiparasitic agent, as a compound capable of reducing HIF-1α, HIF-2α, and HIF-1β protein levels independently of transcript abundance [335].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [335]
Section 3.5 reports that mebendazole reduced HIF-1α, HIF-2α, and HIF-1β protein expression in three breast cancer cell lines under hypoxia. The claim of independence from transcript abundance is too absolute: the same section reports 40% and 30% mRNA reductions for HIF-2α in MCF-7 cells and HIF-1β in SUM159 cells, respectively. No page numbers are available in our copy. (LLM, conf=0.86)
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- Authors
- Joe, N. S., Wang, Y., Oza, H. H., Godet, I., Milki, N., Riggins, G. J., & Gilkes, D. M.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Gilkes, Daniele M.
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2023-02-20
- Volume
- 15
- Issue
- 4
- Pages
- 1330
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC9954103
- OpenAlex
- W4321377499
- Cited by
- 9
- References
- 41
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 1
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- The Jayne Koskinas Ted Giovanis Foundation for Health and Policy
- The Emerson Collective
- The Allegany Health Network
- Virginia & DK Ludwig Fund for Cancer Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Keywords
- mebendazole, breast cancer, hypoxia-inducible factor, HIF-1α, HIF-2α, ARNT, transcriptional activity, hypoxia response, tubulin polymerization inhibitors, gene expression profiling, HIF inhibitors, cancer therapy
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