Cited by 116Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerHeterocyclic Compound Synthesis and Bioactivity

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HIF-1 Inhibitors for Cancer Therapy: From Gene Expression to Drug Discovery

Semenza, G.·2009·Current Pharmaceutical Design

DOI 10.2174/138161209789649402

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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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Annexin A1 sustains tumor metabolism and cellular proliferation upon stable loss of HIF1A
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“The majority of cancer cell lines and experimental tumor models depends on HIF-1 for growth and systemic spread, resulting in the general appreciation of HIF- 1 as an oncoprotein and an attractive target for cancer therapy [40].”
Background
Pleomorphic Carcinoma of the Lung: Relationship Between CT Findings and Prognosis
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“Hypoxia is a characteristic of invasive cancers that can lead to the development of an aggressive phenotype through a mechanism that is mediated mainly by hypoxia-inducible factor (HIF)–1 and that includes cell immortalization and dedifferentiation, pH regulation, autocrine growth and survival, angiogenesis, invasion…”
Hypoxia in the pathogenesis of preeclampsia
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Lactate metabolism and lactylation in breast cancer: mechanisms and implications
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“Lactate generated from tumors stimulates angiogenesis and endothelial cell activation through both HIF-dependent and HIF-independent mechanisms [20, 21].”
Nonalcoholic fatty pancreatic disease and cardio-metabolic risk: is there is a place for obstructive sleep apnea?
Mirrakhimov, A. E. (2014) · Cardiovascular Diabetology · doi:10.1186/1475-2840-13-29 · Cited by 20
“Indeed, the activation of HIF seems to play a key role in the development and pathogenesis of cancer [32-35].”
Background
H2O2 transit through the mitochondrial intermembrane space promotes tumor cell growth in vitro and in vivo
Sabharwal, S. S., Dudley, V. J., Landwerlin, C., & Schumacker, P. T. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104624 · Cited by 18
“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).”
Background
Thyroid Hormone, Cancer, and Apoptosis
Lin, H., Chin, Y., Yang, Y. S. H., Lai, H.-Y., Whang‐Peng, J., Liu, L. F., Tang, H., & Davis, P. J. (2016) · Comprehensive physiology · doi:10.1002/j.2040-4603.2016.tb00712.x · Cited by 17
“The target genes of HIF-1 α protein play key roles in cancer biology, from angiogenesis to adaptation to hypoxia and are actively expressed in rapidly growing tumors, and in invasion and metastasis (146).”
Hypoxic-induced truncation of voltage-dependent anion channel 1 is mediated by both asparagine endopeptidase and calpain 1 activities
Pahima, H. T., Reina, S., Tadmor, N., Dadon-Klein, D., Shteinfer‐Kuzmine, A., Mazure, N. M., Pinto, V. D., & Shoshan‐Barmatz, V. (2018) · Oncotarget · doi:10.18632/oncotarget.24377 · Cited by 17
“In, addition, tumors exposed to a limiting oxygen microenvironment acquire resistance to chemotherapyinduced apoptosis [12, 19, 20] and present reduced responses to radiotherapy [8].”
Background
Stabilization of hypoxia-inducible factor-1α in buffer containing cobalt chloride for Western blot analysis
Srinivasan, S., & Dunn, J. F. (2011) · Analytical Biochemistry · doi:10.1016/j.ab.2011.04.037 · Cited by 17
“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].”
Background
Effects of thyroxine on apoptosis and proliferation of mammary tumors
Zyla, L., Cano, R., Gómez, S., et al. (2021) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2021.111454 · Cited by 16
1, 9-Pyrazoloanthrones Downregulate HIF-1α and Sensitize Cancer Cells to Cetuximab-Mediated Anti-EGFR Therapy
Lü, Y., Li, X., Lu, H., & Fan, Z. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015823 · Cited by 16
“Several strategies for targeting HIF-1a or its upstream regulators or downstream target genes have been tested in recent years [18].”
Background
Reactive oxygen species-responsive theranostic nanoparticles for enhanced hypoxic tumor photodynamic therapy via synchronous HIF-1α inhibition and ATP depletion
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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].”
Background
NOTCH1, HIF1A and Other Cancer-Related Proteins in Lung Tissue from Uranium Miners—Variation by Occupational Exposure and Subtype of Lung Cancer
Pesch, B., Casjens, S., Stricker, I., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045305 · Cited by 15
“HIF1A might also constitute a therapeutic target [34,35].”
Background
The Effect Of Curcumin On Hypoxia In Tumor Microenvironment As a Regulatory Factor In Cancer
Zahedi, M., Izadi, H. S., Arghidash, F., Gumpricht, E., Banach, M., & Sahebkar, A. (2023) · Archives of Medical Science · doi:10.5114/aoms/171122 · Cited by 16
Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma?
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Quantitative proteomic analysis of the inhibitory effects of CIL-102 on viability and invasiveness in human glioma cells
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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).”
Background
Repurposing the anti-parasitic agent pentamidine for cancer therapy; a novel approach with promising anti-tumor properties
Rastegar‐Pouyani, N., Farzin, M. A., Zafari, J., Abdolvahab, M. H., & Hassani, S. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06293-w · Cited by 14
“…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].”
Background
Evaluation of the Betulinic Acid–Cisplatin conjugate APC and its precursor DE9B for the treatment of human malignant glioma
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Modelling reoxygenation effects in non-small cell lung cancer cell lines and showing epithelial-mesenchymal transition
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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.”
Background
Comprehensive Analysis of the Significance of Ferroptosis-Related Genes in the Prognosis and Immunotherapy of Oral Squamous Cell Carcinoma
Yin, J., Zeng, X., Ai, Z., Xu, J., Wu, Y., Jiang, J., Zheng, Z., Shengjiao, L., & Li, J. (2022) · Bioinformatics and Biology Insights · doi:10.1177/11779322221115548 · Cited by 8
Complementary and Alternative Medicine and Cancer Survivorship
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HIF1 and ID1 Interplay Confers Adaptive Survival to HIF1α-Inhibition
Geng, H., Ko, H., Pittsenbarger, J., Harvey, C. T., Xue, C., Liu, Q., Wiens, S., Kachhap, S. K., Beer, T. M., & Qian, D. Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.724059 · Cited by 5
“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).”
Background
Polysaccharide K suppresses angiogenesis in colon cancer cells
SATOH, Y., Goi, T., NAKAZAWA, T., et al. (2012) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2012.632 · Cited by 5
“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).”
HIF-1 inhibitors: differential effects of Acriflavine and Echinomycin on tumor associated CA-IX enzyme and VEGF in melanoma
BEDİR, B. E. Ö., Terzi, E., Şi̇mşek, E., et al. (2021) · Turkish Journal of Biochemistry · doi:10.1515/tjb-2021-0085 · Cited by 4
“Semenza had postulated that using HIF-1 inhibitors can be acted as applicable tumor agents for focusing on VEGF [28].”
Background
Metastasis‐associated gene, mag‐1 improves tumour microenvironmental adaptation and potentiates tumour metastasis
Wang, Y., Jia, H., Lin, H., Tan, X., Du, Z., Chen, H., Xu, Y., Han, X., Zhang, J., Zhao, S., et al. (2012) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2012.01633.x · Cited by 5
Effective oxygen metabolism-based prognostic signature for colorectal cancer
Yuan, Y., Zhang, Z., Ma, B., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1072941 · Cited by 3
Anticancer drugs acting on signaling pathways, part 1: Tyrosine kinase inhibitors
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How to Manipulate Cellular O2 Sensing
Metzen, E., & Schneider, K. (2010) · Chemistry & Biology · doi:10.1016/j.chembiol.2010.04.004 · Cited by 2
“On the other hand, however, it would be attractive to limit angiogenesis and thus blood supply to tumors via HIF inhibition (Semenza, 2009).”
Background
Targeting HIF-1α and HIF-2α to Overcome Treatment Resistance Mediated by Oncogenic KRAS in Colorectal Cancer
Gupta, E., Santos, N., Liu, Y., Havre, P. A., Dang, N. H., Luesch, H., & Dang, L. H. (2013) · Journal of Cancer Therapy · doi:10.4236/jct.2013.46129 · Cited by 1
New Therapeutic Targets in Inflammatory Breast Cancer
Robertson, F. M., & Cristofanilli, M. (2012) · Current Breast Cancer Reports · doi:10.1007/s12609-012-0087-3 · Cited by 1
“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)
DOI: 10.2174/138161209789649402
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 › Heterocyclic Compound Synthesis and Bioactivity
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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HIF-1 Inhibitors for Cancer Therapy: From Gene Expression to Drug Discovery

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