Biol. Pharm. Bull., 29(10),1999-2003, October 2006

Regular Articles

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

Yohko YAMAZAKI,*,a Yuki HASEBE,b Kiyoshi EGAWA,b Kiyoshi NOSE,b Setsuko KUNIMOTO,a and Daishiro IKEDAa

a Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center; 18-24 Miyamoto, Numazu, Shizuoka 410-0301, Japan: and b Department of Microbiology, Showa University of Pharmaceutical Sciences; 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. * To whom correspondence should be addressed. e-mail:

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.

Key words hypoxia-inducible factor-1; anthracycline; vascular endothelial growth factor