Anthracyclines, Small-Molecule Inhibitors of Hypoxia-Inducible Factor-1 Alpha Activation

Hypoxia-inducible factor-1 (HIF-1) is a central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. To identify small molecule inhibitors of the HIF-1 transcriptional activation, we have established a high through-put assay sy...

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Bibliographic Details
Published in:Biological & Pharmaceutical Bulletin 2006, Vol.29(10), pp.1999-2003
Main Authors: Yamazaki, Yohko, Hasebe, Yuki, Egawa, Kiyoshi, Nose, Kiyoshi, Kunimoto, Setsuko, Ikeda, Daishiro
Format: Article
Language:English
Subjects:
Animals
anthracycline
Anthracyclines - pharmacology
CHO Cells
Cricetinae
Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors
hypoxia-inducible factor-1
Promoter Regions, Genetic
RNA, Messenger - analysis
vascular endothelial growth factor
Vascular Endothelial Growth Factor A - genetics
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Summary:Hypoxia-inducible factor-1 (HIF-1) is a central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. To identify small molecule inhibitors of the HIF-1 transcriptional activation, we have established a high through-put assay system using a stable transformant of mammalian cells that express the luciferase reporter gene construct containing a HIF-1 binding site. Using this system, we screened 5000 cultured broths of microorganisms, and we found that cinerubin (1-hydroxy aclacinomycin B) showed a significant inhibition of the reporter activity induced by hypoxic conditions. In addition, we demonstrated that aclarubicin also inhibited the HIF-1 transcriptional activity under hypoxic conditions, but neither doxorubicin nor daunorubicin inhibited it. Consistent with these results, cinerubin and aclarubicin inhibited the hypoxic induction of the vascular endothelial growth factor (VEGF) protein in HepG2 cells, but neither doxorubicin nor daunorubicin affected it. Thus, our results suggested that some anthracyclines are also acting as angiogenesis inhibitors.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.29.1999