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A RNA antagonist of hypoxia-inducible factor-1α, EZN-2968, inhibits tumor cell growth
Open accessAbstract
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that plays a critical role in angiogenesis, survival, metastasis, drug resistance, and glucose metabolism. Elevated expression of the α-subunit of HIF-1 (HIF-1α), which occurs in response to hypoxia or activation of growth factor pathways, is associated with poor prognosis in many types of cancer. Therefore, down-regulation of HIF-1α protein by RNA antagonists may control cancer growth. EZN-2968 is a RNA antagonist composed of third-generation oligonucleotide, locked nucleic acid, technology that specifically binds and inhibits the expression of HIF-1α mRNA. In vitro, in human prostate (15PC3, PC3, and DU145) and glioblastoma (U373) cells, EZN-2968 induced a potent, selective, and durable antagonism of HIF-1 mRNA and protein expression (IC50, 1-5 nmol/L) under normoxic and hypoxic conditions associated with inhibition of tumor cell growth. Additionally, down-regulation of HIF-1α protein by EZN-2968 led to reduction of its transcriptional targets and of human umbilical vein endothelial cell tube formation. In vivo, administration of EZN-2968 to normal mice led to specific, dose-dependent, and highly potent down-regulation of endogenous HIF-1α and vascular endothelial growth factor in the liver. The effect can last for days after administration of single dose of EZN-2968 and is associated with long residence time of locked nucleic acid in certain tissues. In efficacy studies, tumor reduction was found in nude mice implanted with DU145 cells treated with EZN-2968. Ongoing phase I studies of EZN-2968 in patients with advanced malignancies will determine optimal dose and schedule for the phase II program. [Mol Cancer Ther 2008;7(11):3598–608]
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“IC50 values for the HIF-2α isoform, with which EZN-2968 has a 3-base-pair mismatch, were 5 times higher in all cell lines tested compared to IC50 values for HIF-1α, supporting the relative selectivity of EZN-2968 for HIF-1α [11].”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Because preclinical biodistribution studies of EZN-2968 documented prolonged and preferential retention in the liver [11]”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“It was reported that inhibition of HIF-1α by EZN-2698 attenuates HIF-1α protein level and tumor progression in various in vitro (human prostate and glioblastoma cell lines) and in vivo studies52.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“EZN-2698 (1) is an anti-sense oligonucleotide, an RNA antagonist which specifically binds and inhibits the expression of HIF-1α mRNA as well as HIF-1α target genes.”
From HIF-1α pathway: role, regulation and intervention for cancer therapy (2015) · cites this paper as [52]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The in vivo effect of EZN-2968 has also been tested in a subcutaneous prostate cancer cell line xenograft model and, although treatment did not result in a significant reduction in tumor burden, pre-treatment of cells with EZN-2968 prior to injection resulted in a significant reduction in tumor size.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Greenberger et al., 2008
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In vitro, it potently suppresses HIF-1α protein accumulation with IC50 values in the low-nanomolar range (1–5 nM) under both normoxic and hypoxic conditions.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [281]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“EZN-2968 binds specifically to HIF1A mRNA, promoting transcript degradation and inhibiting translation [280,281].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [281]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In preclinical studies, EZN-2968 effectively attenuated transcription of HIF-1 target genes and inhibited hypoxia-driven angiogenesis in multiple cancer models, including prostate cancer, glioblastoma, and DU145 xenografts [281].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [281]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“EZN-2968 is an LNA antisense oligodeoxynucleotide that has been demonstrated to hybridize with HIF-1α mRNA and block HIF-1α protein expression in preclinical models [11].”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Tumor growth inhibition was observed in xenograft models [11].”
From Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors (2014) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“EZN-2968 has a three base pair mismatch with the HIF-2α sequence and, as a consequence, only downregulates HIF-2α mRNA by 20% at 25 nM.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Greenberger et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“EZN-2968 binding leads to HIF-1α mRNA downregulation in a dose-dependent manner and results in near complete inhibition at 5 nM concentrations (Greenberger et al., 2008).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Greenberger et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“EZN-2968 treatment of tumor cells in vitro downregulated HIF-1α protein levels during hypoxia and reduced the growth rate.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Greenberger et al., 2008
The cited source says what the claim attributes to it.
In the citing paper
“Due to a three-nucleotide mismatch, its activity toward EPAS1 (HIF-2α) mRNA is minimal [281].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [281]
The cited source says what the claim attributes to it.
In the citing paper
“EZN-2968 is built on locked nucleic acid (LNA) chemistry, in which a methylene bridge between the 2′-oxygen and 4′-carbon of the ribose ring locks the sugar into a rigid conformation. This structural feature enhances base-pairing affinity, nuclease resistance, and in vivo stability relative to conventional oligonucleotides [[279], [280], [281]].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [281]
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BindingDB Entry 50040848: Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors.
BindingDB (2013) · UC San Diego · doi:10.7270/q26d5v4n
BindingDB (2013) · UC San Diego · doi:10.7270/q2r212p9
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Manipulating the Tumor Microenvironment for Therapeutic Benefit
Bailey, K. M. (2014) · Digital Commons - University of South Florida (University of South Florida)
Metadata
- Authors
- Greenberger, L. M., Horak, I. D., Filpula, D., Sapra, P., Westergaard, M., Frydenlund, H. F., Albæk, C., Schrøder, H., & Ørum, H.
- Affiliations
- Enzon Pharmaceuticals (United States) (US)
- 2Santaris Pharma A/S, Copenhagen, Denmark
- Venue
- Molecular Cancer Therapeutics
- Published
- 2008-11-01
- Volume
- 7
- Issue
- 11
- Pages
- 3598-3608
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2158916045
- Cited by
- 245
- References
- 49
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 12 · 2023: 13 · 2022: 13 · 2021: 19 · 2020: 11 · 2019: 10 · 2018: 8 · 2017: 7 · 2016: 10 · 2015: 12 · 2014: 22 · 2013: 22 · 2012: 25
- FWCI
- 5.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- HIF-1α, HIF-1, RNA interference, locked nucleic acid, prostate cancer, glioblastoma, tumor growth inhibition, angiogenesis, vascular endothelial growth factor, hypoxia
- MeSH terms
- Animals, Antineoplastic Agents, Humans, Liver, Mice, Inbred C57BL, Oligonucleotides, RNA, Messenger, Transcription, Genetic, Transfection, Down-Regulation, Models, Animal, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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