Daily administration of low-dose daunorubicin or doxorubicin inhibits hypoxia-inducible factor 1 and tumor vascularization
Open accessAbstract
Using a hypoxia-inducible factor 1 (HIF-1)-dependent luciferase reporter in Hep3B human hepatocellular carcinoma cells, we screened over 3,000 drugs that have been used in clinical trials and identified multiple anthracyclines as inhibitors of HIF-1 activity. Anthracyclines interfered with the ability of HIF-1 to bind to DNA. Daily injection of tumor-bearing mice with anthracyclines at low dose inhibited expression of the luciferase reporter and HIF-1 target genes that encode vascular endothelial growth factor A (VEGFA; ligand of VEGFR2), stromal-derived factor 1 (SDF-1; ligand of CXCR4), and stem cell factor (SCF; ligand of CD117) in tumor tissue. Increased numbers of circulating CXCR4 + /Sca1 + , VEGFR2 + /CD34 + , and VEGFR2 + /CD117 + cells were demonstrated in immunodeficient mice bearing prostate cancer xenografts but not in tumor-bearing mice treated with anthracyclines, which also significantly inhibited angiogenesis in tumor tissue. Our findings indicate that HIF-1 inhibition underlies the anti-angiogenic effect associated with daunorubicin or doxorubicin metronomic therapy and suggest that these drugs may be particularly effective in patients with high levels of HIF-1α in their diagnostic tumor biopsy.
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In tumor-bearing mice, chronic administration of anthracyclines at low doses suppresses HIF-1-dependent gene expression and angiogenesis.
“In tumor-bearing mice, chronic administration of anthracyclines at low doses suppresses HIF-1-dependend gene expression and angiogenesis [395].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [395]
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“ChIP was performed with the ChIP Assay kit (Upstate–Cell Signaling Solution) using rabbit polyclonal anti-HIF-1a or anti-HIF-2α antibodies (Novus Biologicals) and normal rabbit IgG as a negative control (Santa Cruz Biotechnology).”
BackgroundInfluentialDigoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth
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BackgroundMethodInfluentialSelf-citationPharmacologic Targeting of Hypoxia-Inducible Factors
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HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
- Authors
- Yang, Y., Qian, D. Z., Rey, S., Liu, J. O., & Semenza, G. L.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, Gregg L.
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2022-06-17
- OpenAlex
- W4283014037
- Cited by
- 2
- References
- 4
- Citations by year
- 2025: 2
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- Flight Attendant Medical Research Institute
- Johns Hopkins University
- 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
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- HIF-1, HIF-1 inhibition, daunorubicin, doxorubicin, anthracyclines, metronomic chemotherapy, tumor angiogenesis, tumor vascularization, hepatocellular carcinoma, prostate cancer xenografts, VEGF-A, CXCR4, VEGFR2, stem cell factor, HIF-1 target genes, angiogenesis inhibition
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