title: 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.
authors.affiliation: Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Miyamoto, Shizuoka, Japan. yamako@bikaken.or.jp
authors.forename: Yohko
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hasebe
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Egawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Nose
authors.forename: Setsuko
authors.initials: S
authors.lastname: Kunimoto
authors.forename: Daishiro
authors.initials: D
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D018943:Anthracyclines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A