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Cited by 125Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerBioactive Compounds and Antitumor Agents

Reversing hypoxic cell chemoresistance in vitro using genetic and small molecule approaches targeting hypoxia inducible factor-1

Brown, Louisa M., Cowen, Rachel L., Debray, Camille, Eustace, Amanda, Erler, Janine T., Sheppard, Freda CD., Parker, Catriona A., Stratford, Ian J. +1 more·2006·Molecular Pharmacology
DOI 10.1124/mol.105.015743
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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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  • HIF1/2 inhibitors might be effective in combination with conventional chemotherapy.

    “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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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)
ORCID
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2006-02
Volume
69
Issue
2
Pages
411-418
ISSN
0026-895X (ISSN-L)
DOI
10.1124/mol.105.015743
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
Licence
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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