Inhibition of angiogenesis and HIF-1alpha activity by antimycin A1.
We identified antimycin A1 as an inhibitor of the hypoxia-response element (HRE) from screening using a reporter under the control of HRE under hypoxic conditions. Antimycin A1 was effective at 20 pg/ml in inhibiting the reporter activity. The expression of vascular endothelial growth factor (VEGF) mRNA during hypoxia was also inhibited by antimycin A1. Angiogenesis induced by implantation of mouse sarcoma-180 cells was significantly inhibited by non-toxic doses of antimycin A1. Hypoxia inducible factor (HIF)-1alpha protein levels were significantly decreased by antimycin A1, but its mRNA level was not affected. Antimycin A1 is known to be an inhibitor of mitochondrial electron transport system, and depletion of mitochondria abolished antimycin A1-effect, at least in part. Inhibitors of proteasome or protein synthesis did not affect the decrease in HIF-1alpha level induced by antimycin A1. These results indicate that antimycin A1 inhibited angiogenesis through decrease in VEGF production caused by inhibition of HIF-1alpha activation.
Maeda
Masayuki
M
Department of Microbiology, Showa University of Pharmaceutical Sciences, Tokyo, Japan.
Hasebe
Yuki
Y
Egawa
Kiyoshi
K
Shibanuma
Motoko
M
Nose
Kiyoshi
K
D000818:Animals; D000968:Antimycin A / Q000494:pharmacology*; D016466:CHO Cells; D015687:Cell Hypoxia; D003001:Cloning, Molecular; D006224:Cricetinae; D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D017931:DNA Primers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D000968:Antimycin A