Anthracyclines, small-molecule inhibitors of hypoxia-inducible factor-1 alpha activation.

Abstract:

: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.

journal_name

Biol Pharm Bull

authors

Yamazaki Y,Hasebe Y,Egawa K,Nose K,Kunimoto S,Ikeda D

doi

10.1248/bpb.29.1999

subject

Has Abstract

pub_date

2006-10-01 00:00:00

pages

1999-2003

issue

10

eissn

0918-6158

issn

1347-5215

pii

JST.JSTAGE/bpb/29.1999

journal_volume

29

pub_type

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