Abstract | PURPOSE:
Adaphostin was developed as an inhibitor of the p210(bcr-abl) tyrosine kinase, but as its activity is not limited to tumor cell lines containing this translocation, transcriptional profiling was used as a tool to elucidate additional mechanisms responsible for adaphostin cytotoxicity. EXPERIMENTAL DESIGN: Profiles of drug-induced transcriptional changes were measured in three hematopoietic cell lines following 1 and 10 micromol/L adaphostin for 2 to 6 hours and then confirmed with real-time reverse transcription-PCR (2-24 hours). These data indicated altered iron homeostasis, and this was confirmed experimentally. Alteration of vascular endothelial growth factor ( VEGF) secretion through hypoxia-inducible factor-1 (HIF-1) regulation was also investigated. RESULTS: CONCLUSIONS:
Adaphostin-induced cytotoxicity is caused in part by a rapid release of free iron, leading to redox perturbations and cell death. Despite this, reduced VEGF secretion was found to be independent of regulation by the redox responsive transcription factor HIF-1. Thus, adaphostin remains an interesting agent with the ability to kill tumor cells directly and modulate angiogenesis.
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Authors | Curtis Hose, Gurmeet Kaur, Edward A Sausville, Anne Monks |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 11
Issue 17
Pg. 6370-81
(Sep 01 2005)
ISSN: 1078-0432 [Print] United States |
PMID | 16144942
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Antioxidants
- Culture Media, Conditioned
- Drug Combinations
- HIF1A protein, human
- Hydroquinones
- Hypoxia-Inducible Factor 1, alpha Subunit
- Iron Chelating Agents
- NSC 680410
- RNA, Messenger
- Receptors, Transferrin
- Transcription Factors
- VEGFA protein, human
- Vascular Endothelial Growth Factor A
- Iron
- Adamantane
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Topics |
- Adamantane
(analogs & derivatives, pharmacology)
- Antioxidants
(pharmacology)
- Cell Hypoxia
- Culture Media, Conditioned
(pharmacology)
- Drug Combinations
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- HL-60 Cells
- Humans
- Hydroquinones
(pharmacology)
- Hypoxia-Inducible Factor 1, alpha Subunit
- Iron
(metabolism)
- Iron Chelating Agents
(pharmacology)
- Jurkat Cells
- K562 Cells
- Molecular Structure
- Oligonucleotide Array Sequence Analysis
- Oxidative Stress
- RNA, Messenger
(genetics, metabolism)
- Receptors, Transferrin
(metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription Factors
(pharmacology)
- Transcription, Genetic
(drug effects)
- Vascular Endothelial Growth Factor A
(metabolism)
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