Inhibition of angiogenesis and HIF-1α activity by antimycin A1

We identified antimycin Al as an inhibitor of the hypoxia-response element (HRE) from screening using a reporter under the control of HRE under hypoxic conditions. Antimycin Al 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 Al. Angiogenesis induced by implantation of mouse sarcoma-180 cells was significantly inhibited by non-toxic doses of antimycin Al. Hypoxia inducible factor (HIF)-1 alpha protein levels were significantly decreased by antimycin Al, but its mRNA level was not affected. Antimycin Al is known to be an inhibitor of mitochondrial electron transport system, and depletion of mitochondria abolished antimycin Al-effect, at least in part. Inhibitors of proteasome or protein synthesis did not affect the decrease in HIF-1 alpha level induced by antimycin Al. These results indicate that antimycin Al inhibited angiogenesis through decrease in VEGF production caused by inhibition of HIF-1 alpha activation.