HIF-1 Inhibitors for Cancer Therapy: From Gene Expression to Drug Discovery
Abstract
Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric protein composed of HIF-1alpha and HIF-1alpha subunits, which is activated in response to reduced O2 availability. HIF-1 transactivates genes encoding proteins that are involved in key aspects of the cancer phenotype, including cell immortalization and de-differentiation, stem cell maintenance, genetic instability, glucose uptake and metabolism, pH regulation, autocrine growth/survival, angiogenesis, invasion/metastasis, and resistance to chemotherapy. Increased HIF-1alpha levels, as determined by immunohistochemical analysis of tumor biopsy specimens, is associated with increased mortality in many human cancers. Drugs that inhibit HIF-1 activity and have anti-cancer effects in vivo have been identified and clinical trials are warranted to establish the contexts in which addition of such agents to therapy protocols will result in increased patient survival.
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A number of molecules that impair HIF at various transcriptional and translational stages have been identified.
“The search for possible HIF inhibitors has led to the identification of a number of molecules that impair HIF at various transcriptional and translational stages (ranging from protein stabilization to dimerization to DNA binding) [123].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [123]
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“These signals promote the stabilization of HIF-1α; subsequent HIF transcriptional activity leads to the expression of multiple genes that contribute to cancer cell survival, altered metabolism, migration, and metastatic phenotype (34, 35).”
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“In, addition, tumors exposed to a limiting oxygen microenvironment acquire resistance to chemotherapyinduced apoptosis [12, 19, 20] and present reduced responses to radiotherapy [8].”
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“Numerous reports suggest that HIF-1α and its target genes could be important mediators of hypoxia-induced ischemic tolerance and an important target in therapeutics [1–5].”
BackgroundEffects of thyroxine on apoptosis and proliferation of mammary tumors
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“Several strategies for targeting HIF-1a or its upstream regulators or downstream target genes have been tested in recent years [18].”
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Metabolic Targeting of Malignant Tumors: Small-Molecule Inhibitors of Bioenergetic Flux
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“Thus, it has become a marked target for anticancer therapy, both at pre-clinical and clinical stages [50].”
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“HIF1A might also constitute a therapeutic target [34,35].”
BackgroundThe Effect Of Curcumin On Hypoxia In Tumor Microenvironment As a Regulatory Factor In Cancer
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“…compounds are believed to be due at least in part to the induction of cellular molecular targets including the prooxidant and glycolytic pathway, as well as the inhibition of cell viability and aggressive signaling pathways culminating in cell cycle arrest and/or cell death (Semenza, 2009).”
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“…agents, such as small molecules (FM19G11, IDF-11774, and KC7F2), monoclonal antibodies (mAbs) (cetuximab and trastuzumab), siRNAs, and histone deacetylase inhibitors (apigenin, trichostatin A, and suberoylanilide hydroxamic acid), and nanobodies, have been suggested to target this protein [87–89].”
Role of nuclear receptors in breast cancer stem cells
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“of cancer cells, such as angiogenesis, invasion, drug resistance, increased cell proliferation, and reduced apoptosis [9,10].”
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“This oxygen fluctuation activates survival pathways and is thought to contribute to cancer cell resistance to chemo and radiotherapies (Semenza 2009; Noman et al.”
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Complementary and Alternative Medicine and Cancer Survivorship
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HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition
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“Clinically, an increase of HIF1α level is associated with advanced metastatic disease and/or patient mortality in almost all types of solid tumors (Semenza, 2007, 2009, 2010, 2012).”
BackgroundPolysaccharide K suppresses angiogenesis in colon cancer cells
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“We investigated how the addition of PSK to the medium of cultured colon cancer cell lines affects the expression of the HIF-1α gene, which is closely associated with the expression of angiogenic growth factors, in addition to angiogenic growth factors and angiogenesis (18-23).”
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“Semenza had postulated that using HIF-1 inhibitors can be acted as applicable tumor agents for focusing on VEGF [28].”
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Effective oxygen metabolism-based prognostic signature for colorectal cancer
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Anticancer drugs acting on signaling pathways, part 1: Tyrosine kinase inhibitors
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How to Manipulate Cellular O2 Sensing
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“On the other hand, however, it would be attractive to limit angiogenesis and thus blood supply to tumors via HIF inhibition (Semenza, 2009).”
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New Therapeutic Targets in Inflammatory Breast Cancer
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“Given the demonstrated importance of HIF1α as a therapeutic target, and the identification of FDA-approved agents such as the cardiac glycoside digoxin that target HIF1α [51], we are currently investigating HIF1α as a potential therapeutic target for use in clinical trials with IBC patients.”
BackgroundInfluential
- Authors
- Semenza, G.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Semenza, G.
- ORCID
- Semenza, G.
- Venue
- Current Pharmaceutical Design
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2009-11-01
- Volume
- 15
- Issue
- 33
- Pages
- 3839-3843
- ISSN
- 1381-6128 (ISSN-L)
- OpenAlex
- W2077230187
- Cited by
- 116
- References
- 0
- Citations by year
- 2025: 3 · 2024: 4 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 14 · 2015: 3 · 2014: 11 · 2013: 9 · 2012: 14
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Pharmaceutical Design (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- National Institute of General Medical Sciences
- 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
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- HIF-1, HIF-1 inhibitors, HIF-1α, tumor hypoxia, cancer therapy, drug discovery, angiogenesis, metastasis, chemoresistance, glucose metabolism, stem cell maintenance, gene expression
- MeSH terms
- Antineoplastic Agents, Humans, Neoplasms, Drug Design, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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