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Reversing Hypoxic Cell Chemoresistance in Vitro Using Genetic and Small Molecule Approaches Targeting Hypoxia Inducible Factor-1
Abstract
The resistance of hypoxic cells to conventional chemotherapy is well documented. Using both adenovirus-mediated gene delivery and small molecules targeting hypoxia-inducible factor-1 (HIF-1), we evaluated the impact of HIF-1 inhibition on the sensitivity of hypoxic tumor cells to etoposide. The genetic therapy exploited a truncated HIF-1alpha protein that acts as a dominant-negative HIF-1alpha (HIF-1alpha-no-TAD). Its functionality was validated in six human tumor cell lines using HIF-1 reporter assays. An EGFP-fused protein demonstrated that the dominant-negative HIF-1alpha was nucleus-localized and constitutively expressed irrespective of oxygen tension. The small molecules studied were quinocarmycin monocitrate (KW2152), its analog 7-cyanoquinocarcinol (DX-52-1), and topotecan. DX-52-1 and topotecan have been previously established as HIF-1 inhibitors. HT1080 and HCT116 cells were treated with either AdHIF-1alpha-no-TAD or nontoxic concentrations (0.1 microM; <IC(10)) of KW2152 and DX-52-1 and exposed to etoposide in air or anoxia (<0.01% oxygen). Topotecan inhibited HIF-1 activity only at cytotoxic concentrations and was not used in the combination study. Etoposide IC(50) values in anoxia were 3-fold higher than those in air for HT1080 (2.2 +/- 0.3 versus 0.7 +/- 0.2 microM) and HCT116 (9 +/- 4 versus 3 +/- 2 microM) cells. KW2152 and DX-52-1 significantly reduced the anoxic etoposide IC(50) in HT1080 cells, whereas only KW2152 yielded sensitization in HCT116 cells. In co…
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“Taken together, these data on the role of HIFs in therapeutic resistance suggest that HIF1/2 inhibitors might be effective in combination with conventional chemotherapy (Unruh et al., 2003;Erler et al., 2004;Brown et al., 2006;Nardinocchi et al., 2009;Roberts et al., 2009;He et al., 2012;Zhao et al., 2014).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Brown et al., 2006
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Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy
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Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer
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“…these data on the role of HIFs in therapeutic resistance suggest that HIF1/2 inhibitors might be effective in combination with conventional chemotherapy (Unruh et al., 2003; Erler et al., 2004; Brown et al., 2006; Nardinocchi et al., 2009; Roberts et al., 2009; He et al., 2012; Zhao et al., 2014).”
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Metadata
- Authors
- Brown, L. M., Cowen, R. L., Debray, C., Eustace, A., Erler, J. T., Sheppard, F. C., Parker, C. A., Stratford, I. J., & Williams, K. J.
- Affiliations
- University of Manchester (GB)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 69
- Issue
- 2
- Pages
- 411-418
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2148419067
- Cited by
- 125
- References
- 40
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 6 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 4 · 2015: 8 · 2014: 9 · 2013: 9 · 2012: 9
- FWCI
- 2.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Funders
- National Cancer Institute (T32CA009151)
- 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 › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- HIF-1, HIF-1α, etoposide sensitivity, topotecan, HIF-1 inhibitors, adenoviral gene transfer, tumor hypoxia, anoxia
- MeSH terms
- Adenoviridae, Antineoplastic Agents, Phytogenic, Cell Nucleus, Etoposide, Genetic Vectors, Humans, Isoquinolines, Neoplasms, Oxygen, Transcriptional Activation, Cell Hypoxia, Sequence Deletion, Drug Resistance, Neoplasm, Topotecan, Cell Line, Tumor, Green Fluorescent Proteins, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit
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