Reversing Hypoxic Cell Chemoresistance in Vitro Using Genetic and Small Molecule Approaches Targeting Hypoxia Inducible Factor-1
| Autor: | Louisa M. Brown, Kaye J. Williams, Freda C. D. Sheppard, Camille Debray, Amanda Eustace, Janine T. Erler, Ian J. Stratford, Rachel L. Cowen, Catriona Parker |
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| Rok vydání: | 2005 |
| Předmět: |
Transcriptional Activation
Genetic Vectors Green Fluorescent Proteins Gene delivery Biology Adenoviridae Cell Line Tumor Neoplasms medicine Humans Cytotoxic T cell Etoposide Sequence Deletion Cell Nucleus Pharmacology Hypoxia-Inducible Factor 1 alpha Subunit Isoquinolines Antineoplastic Agents Phytogenic Molecular biology Cell Hypoxia In vitro Oxygen tension Oxygen Drug Resistance Neoplasm Cell culture Molecular Medicine HT1080 Topotecan Hypoxia-Inducible Factor 1 medicine.drug |
| Zdroj: | Molecular Pharmacology. 69:411-418 |
| ISSN: | 1521-0111 0026-895X |
| DOI: | 10.1124/mol.105.015743 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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