Anthracycline Inhibits Recruitment of Hypoxia-inducible Transcription Factors and Suppresses Tumor Cell Migration and Cardiac Angiogenic Response in the Host
Open accessAbstract
Anthracycline chemotherapeutic agents of the topoisomerase inhibitor family are widely used for the treatment of various tumors. Although targeted tumor tissues are generally situated in a hypoxic environment, the connection between efficacy of anthracycline agents and cellular hypoxia response has not been investigated in depth. Here, we report that doxorubicin (DXR) impairs the transcriptional response of the hypoxia-inducible factor (HIF) by inhibiting the binding of the HIF heterodimer to the consensus -RCGTG- enhancer element. This pleiotropic effect retarded migration of von Hippel-Lindau (VHL)-defective renal cell carcinoma and that of VHL-competent renal cell carcinoma in hypoxia. This effect was accompanied by a coordinated down-regulation of HIF target lysyl oxidase (LOX) family members LOX, LOX-like2 (LOXL2), and LOXL4. Furthermore, DXR suppressed HIF target genes in tumor xenografts, inhibited cardiac induction of HIF targets in rats with acute anemia, and impaired the angiogenic response in the isoproterenol-induced heart failure model, which may account for the clinical fragility of doxorubicin cardiomyopathy. Collectively, these findings highlight the impaired hypoxia response by anthracycline agents affecting both tumors and organs of the cancer host and offer a promising opportunity to develop HIF inhibitors using DXR as a chemical template.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Anthracyclines, including doxorubicin, daunorubicin, epirubicin, and idarubicin, disrupt binding of HIF-1α and HIF-2α to DNA.
“Anthracyclines, including doxorubicin, daunorubicin, epirubicin, and idarubicin, disrupt binding of HIF-1α and HIF-2α to DNA [393,394].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [393]
The Results report that doxorubicin reduced HIF-1α binding to target-gene promoters; they also report reduced HIF-2 activity and reduced HIF-responsive reporter activity with daunorubicin. Those latter findings do not directly establish disrupted DNA binding by both HIF isoforms for each drug. Our copy does not address epirubicin or idarubicin (searched both names). (LLM, conf=0.88)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 33 · Cited by 50
Research works printed but not linked: 2
- Bernhardt, W. M., Gottmann, U., Doyon, F., Buchholz, B., Campean, V., Schödel, J., Reisenbuechler, A., Klaus, S., Arend, M., Flippin, L., Willam, C., Wiesener, M. S., Yard, B., Warnecke, C., and Eckardt, K. U. (2009) Donor treatment with a PHD-inhibitor activating HIFs prevents graft injury and prolongs survival in an allogenic kidney transplant model. Proc. Natl. Acad. Sci. U.S.A. 106, 21276 -21281
- Lee, K., Qian, D. Z., Rey, S., Wei, H., Liu, J. O., and Semenza, G. L. (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc. Natl. Acad. Sci. U.S.A. 106, 2353-2358
- Authors
- Tanaka, T., Yamaguchi, J., Shoji, K., & Nangaku, M.
- Affiliations
- The University of Tokyo (JP)
- Corresponding author
- Tanaka, Tetsuhiro
- Nangaku, Masaomi
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 287
- Issue
- 42
- Pages
- 34866-34882
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3471702
- OpenAlex
- W2022433397
- Cited by
- 50
- References
- 33
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 5 · 2015: 7 · 2014: 3 · 2013: 4
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation
- Japan Society for the Promotion of Science (24390213, 22790781)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Chemotherapy-induced cardiotoxicity and mitigation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- anthracyclines, doxorubicin, hypoxia-inducible factor, tumor cell migration, lysyl oxidase, LOX, LOXL2, LOXL4, cardiac angiogenesis, doxorubicin cardiomyopathy, HIF inhibitors, topoisomerase inhibitors, tumor xenografts, isoproterenol-induced heart failure
- MeSH terms
- Amino Acid Oxidoreductases, Animals, Antibiotics, Antineoplastic, Carcinoma, Renal Cell, Cell Movement, Doxorubicin, HeLa Cells, Humans, Kidney Neoplasms, Protein-Lysine 6-Oxidase, Mice, Nude, Cardiomyopathies, Myocardium, Neoplasm Proteins, Neoplasm Transplantation, Neovascularization, Pathologic, Transplantation, Heterologous, Cell Hypoxia, Rats, Sprague-Dawley, Response Elements, Mice, Rats, Hypoxia-Inducible Factor 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
