Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy
Open accessAbstract
Hypoxia-inducible factor-1 (HIF-1) has been reported to promote tumour radioresistance; therefore, it is recognised as an excellent target during radiation therapy. However, the inhibition of HIF-1 in unsuitable timing can suppress rather than enhance the effect of radiation therapy because its anti-angiogenic effect increases the radioresistant hypoxic fraction. In this study, we imaged changes of HIF-1 activity after treatment with radiation and/or an HIF-1 inhibitor, YC-1, and optimised their combination. Hypoxic tumour cells were reoxygenated 6 h postirradiation, leading to von Hippel-Lindau (VHL)-dependent proteolysis of HIF-1alpha and a resultant decrease in HIF-1 activity. The activity then increased as HIF-1alpha accumulated in the reoxygenated regions 24 h postirradiation. Meanwhile, YC-1 temporarily but significantly suppressed HIF-1 activity, leading to a decrease in microvessel density and an increase in tumour hypoxia. On treatment with YC-1 and then radiation, the YC-1-mediated increase in tumour hypoxia suppressed the effect of radiation therapy, whereas on treatment in the reverse order, YC-1 suppressed the postirradiation upregulation of HIF-1 activity and consequently delayed tumour growth. These results indicate that treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the therapeutic effect of radiation, and the suppression of the postirradiation upregulation of HIF-1 activity is important for the best therapeutic benefit.
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ROS production later stabilizes the HIF-1α protein and increases expression of HIF-1α and its target genes.
“ROS production later stabilizes the HIF-1α protein and increases expression of HIF-1α and its target genes (Moeller et al., 2004;Dewhirst et al., 2008;Harada et al., 2009).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Harada et al., 2009
The Discussion (page not provided) says radiation-induced reoxygenation forms ROS that stabilizes and accumulates HIF-1α protein, and reports increased HIF-1 activity after irradiation. It also says ROS-mediated stabilization alone is insufficient for that activation without newly translated HIF-1α; the claim omits this qualification and does not establish that ROS alone increases expression of HIF-1α and its target genes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAdministration of YC-1 post radiotherapy reduces radiation-induced HIF-1 activation and attenuates tumor expansion in mouse xenograft models of cervical cancer, whereas pretreatment exacerbates hypoxia and diminishes radiotherapy efficacy.
“Administration post radiotherapy reduces radiation-induced HIF-1 activation and attenuates tumor expansion in mouse xenograft models of cervical cancer, whereas pretreatment exacerbates hypoxia and diminishes radiotherapy efficacy [404].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [404]
The Results (page unavailable) report that YC-1 given 1 minute after irradiation suppressed radiation-induced HIF-1 activation and delayed growth of HeLa tumour xenografts. Giving it 5 days before irradiation increased hypoxia and reduced radiotherapy efficacy. The claim omits that timing qualification: YC-1 given 18 hours before irradiation had no significant effect on radiotherapy efficacy, so the adverse result does not apply to pretreatment generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSilencing or pharmacological inhibition of HIF-1α can increase the anti-tumor effects of IR.
“Importantly, silencing or pharmacological inhibition of HIF-1α can increase the anti-tumor effects of IR (Zhang et al., 2004;Moeller et al., 2005;Harada et al., 2009;Harada et al., 2012).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Harada et al., 2009
HIF-1α expression is temporarily and acutely decreased after IR due to re-oxygenation of surviving hypoxic tumor cells.
“HIF-1α expression is temporarily and acutely decreased after IR due to re-oxygenation of surviving hypoxic tumor cells (Harada et al., 2009).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Harada et al., 2009
The timing of YC-1 administration strongly influences therapeutic outcome.
“Notably, the timing of YC-1 administration strongly influences therapeutic outcome.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [404]
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Self-citation
- Authors
- Harada, H., Itasaka, S., Zhu, Y., Zeng, L., Xie, X., Morinibu, A., Shinomiya, K., & Hiraoka, M.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Harada, H
- Venue
- British Journal of Cancer
- Published
- 2009-02-17
- Volume
- 100
- Issue
- 5
- Pages
- 747-757
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC2653764
- OpenAlex
- W1992319933
- Cited by
- 82
- References
- 28
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 6 · 2012: 10
- FWCI
- 2.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science
- 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 › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- HIF-1, HIF-1 inhibitors, YC-1, radiotherapy, tumor hypoxia, radioresistance (biology), treatment sequencing, VHL, tumor reoxygenation, angiogenesis inhibition, microvessel density, tumor growth
- MeSH terms
- Animals, Furans, HeLa Cells, Humans, Indazoles, Neoplasms, Oxygen Consumption, Radiation Tolerance, Radiation-Protective Agents, Radiation-Sensitizing Agents, Tumor Cells, Cultured, Cell Hypoxia, Mice, SCID, Treatment Outcome, Xenograft Model Antitumor Assays, Mice, Hypoxia-Inducible Factor 1
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