Cancer esearch apeutics , Targets , and Chemical Biology inoflavone , a Ligand of the Aryl Hydrocarbon Receptor , R bits HIF-1 α Expression in an AhR-Independent Fashion

Downloa inoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1β/AhR, which is shared with HIF-1α, scription factor critical for the response of cells to oxygen deprivation. To address whether pharmacoctivation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the of AF on HIF-1 expression. AF inhibited HIF-1α transcriptional activity and protein accumulation in cells. However, inhibition of HIF-1α by AF was independent from a functional AhR pathway. Indeed, AF ed HIF-1α expression in Ah cells, in which the AhR pathway is functionally impaired, yet did not cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. MoreF was inactive in MDA-MB-231 cells, yet inhibited HIF-1α in MDA-MB-231 cells transfected with the A1 gene. AF inhibited HIF-1αmRNA expression by ∼50%. Notably, actinomycin-D completely abrogated ility of AF to downregulate HIF-1α mRNA, indicating that active transcription was required for the tion of HIF-1α expression. Finally, AF inhibited HIF-1α protein accumulation and the expression of target genes in MCF-7 xenografts. These results show that AF inhibits HIF-1α in an AhR-independent HIF-1 fashion, and they unveil additional activities of AF that may be relevant for its further clinical development. Cancer Res; 70(17); 6837–48. ©2010 AACR.