Hypoxia inducible factor-1α as a cancer drug target
Open accessAbstract
The hypoxia inducible factor 1 (HIF-1) is a heterodimeric transcription factor that is an important regulator of the growing tumor's response to hypoxia. HIF-1 activity in tumors depends on the availability of the HIF-1α subunit, the levels of which increase under hypoxic conditions and through the activation of oncogenes and/or inactivation of tumor suppressor genes. HIF-1 activates genes that allow the cancer cell to survive and grow in the hostile hypoxic tumor environment. Increased tumor HIF-1α has been correlated with increased angiogenesis, aggressive tumor growth, and poor patient prognosis, leading to the current interest in HIF-1α as a cancer drug target. A number of anticancer agents have been reported to decrease HIF-1α or HIF-1 transactivating activity in cells in culture. However, more relevant to the agents' antitumor activity is whether HIF-1 is inhibited in tumors in vivo. This has been demonstrated for only a few of the reported HIF-1 inhibitors. Some of the agents are moving toward clinical trial where it will be important to demonstrate that the agents inhibit HIF-1α in patient tumors or, failing this, the downstream consequences of HIF-1 inhibition such as decreased vascular endothelial growth factor formation, and relate this inhibition to antitumor activity. Only in this way will it be possible to determine if HIF-1α is a valid cancer drug target in humans.
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Activated HIF-1 plays a crucial role in adaptive responses of tumor cells to changes in oxygen through transcriptional activation of over 100 downstream genes.
“Activated HIF-1 plays a crucial role in adaptive responses of the tumor cells to changes in oxygen through transcriptional activation of over 100 downstream genes which regulate vital biological processes required for tumor survival and progression.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [2]
The Hypoxia Inducible Transcription Factor section describes HIF-1 as a major mediator of responses to reduced oxygen and says it controls genes involved in adaptation and tumor growth. The Conclusions likewise link HIF-1-dependent gene activation to cancer-cell survival and progression. Neither passage gives the claimed count of over 100 downstream genes; a search for that count found no supporting passage in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCurrent approaches seek to suppress HIF activity by reducing HIF-α protein levels, preventing heterodimer formation, or disrupting HIF-DNA interactions.
“Current approaches seek to suppress HIF activity by reducing HIF-α protein levels, preventing heterodimer formation, or disrupting HIF–DNA interactions [[37], [38], [39]]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [38]
The ‘HIF-1A Inhibitors as Anticancer Drugs’ section reports agents that lower HIF-1α protein levels and one that reduces HIF-1 DNA-binding activity. The copy describes HIF-1 as a heterodimer, but does not identify preventing heterodimer formation as an inhibitory approach. Page numbers were not supplied. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHypoxia is common in many types of solid tumors.
“Hypoxia is common in many types of solid tumors, where tumor cells proliferate rapidly and form large solid tumor masses, leading to obstruction and compression of the blood vessels surrounding these masses.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [2]
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References 66 · Cited by 311
Research works printed but not linked: 3
- [15]15. Srinivas V, Zhu X, Salceda S, Nakamura R, Caro J. Hypoxia-inducible factor 1a (HIF-1a) is a non-hemeiron protein. Implications for oxygen sensing. J Biol Chem 1998;273:18019 -22.
- [19]19. Zhong H, De Marco A, Laughner E, et al. Over-expression of hypoxia- inducible factor 1a in common human cancers and metastases. Cancer Res 1999;59:5830 -5.
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- Authors
- Powis, G., & Kirkpatrick, L.
- Affiliations
- University of Arizona (US)
- 2ProlX Pharmaceuticals, Tucson, Arizona
- ORCID
- Powis, Garth
- Venue
- Molecular Cancer Therapeutics
- Published
- 2004-05-01
- Volume
- 3
- Issue
- 5
- Pages
- 647-654
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W1830307401
- Cited by
- 311
- References
- 66
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 15 · 2023: 8 · 2022: 13 · 2021: 10 · 2020: 9 · 2019: 12 · 2018: 11 · 2017: 17 · 2016: 18 · 2015: 19 · 2014: 23 · 2013: 13 · 2012: 14
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA CA052995, CA098920, R01CA098920)
- 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 › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- hypoxia-inducible factor-1α, HIF-1, cancer drug targets, tumor hypoxia, angiogenesis, vascular endothelial growth factor, HIF-1 inhibitors, anticancer activity, oncogene activation, tumor suppressor inactivation, clinical trials
- MeSH terms
- Antineoplastic Agents, Humans, Neoplasms, Transcription Factors, Signal Transduction, Transcriptional Activation, Cell Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit
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