Kamebakaurin inhibits the expression of hypoxia-inducible factor-lα in vitro or in vivo tumor cells

Aim Hypoxia-inducible factor 1 （HIF-1） , a heterodimeric transcription factor that mediates the adap- tation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Kamebakaurin is a diterpenoid compound isolated from Isodonexcia （Maxin.） Hara, which has been used for anti-inflammatory activities. But its antitumor activity has not been reported. Kamebakaurin showed the potent inhibitory activity against HIF-1 activation by COC12 induced hypoxia in various human cancer cell lines. This compound significantly decreased the hypoxia-induced accumulation of HIF-lot protein, whereas it did not af- fect the expressions of topoisomerase-I （Topo-I）. Further analysis revealed that kamebakaurin inhibited HIF-lα protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-lα protein. Fur- thermore, kamebakaurin prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor （VEGF） and erythropoietin （EPO）. However, kamebakaurin caused cell growth inhibition via cell cycle ar- rest at G1 in tumor cells. In vivo studies, we further confirmed the inhibitory effect of kamebakaurin on the expres- sion of HIF-lα proteins, leading to a decrease growth of HCT116 cells in a xenograft tumor model. These resultsshow that kamebakaurin is an effective inhibitor of HIF-1 and provide new perspectives into its anticancer activity.