A novel benzimidazole analogue inhibits the hypoxia-inducible factor (HIF)-1 pathway

Mi Sun Won, Namhui Im, Soohyun Park, Shanthaveerappa K. Boovanahalli, Yinglan Jin, Xuejun Jin, Kyung Sook Chung, Moorim Kang, Kiho Lee, Song Kyu Park, Hwan Mook Kim, Byoung Mog Kwon, Jung Joon Lee, Kyeong Lee

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Hypoxia-inducible factor (HIF)-1 is a therapeutic target in solid tumors. We report the novel benzimidazole analogue AC1-004, obtained from a chemical library using an HRE-dependent cell-based assay in colorectal carcinoma HCT-116 cells. The accumulation of hypoxia-induced HIF-1α was inhibited by compound AC1-004 in various cancer cells, including HCT-116, MDA-MB435, SK-HEP1, and Caki-1. Further, AC1-004 down-regulated VEGF and EPO, target genes of HIF-1, and inhibited in vitro tube formation of HUVEC, suggesting its potential inhibitory activity on angiogenesis. Importantly, AC1-004 was found to regulate the stability of HIF-1α through the Hsp90-Akt pathway, leading to the degradation of HIF-1α. An in vivo antitumor study demonstrated that AC1-004 reduced tumor size significantly (i.e., by 58.6%), without severe side effects. These results suggest the benzimidazole analogue AC1-004 is a novel HIF inhibitor that targets HIF-1α via the Hsp90-Akt pathway, and that it can be used as a new lead in developing anticancer drugs.

Original languageEnglish
Pages (from-to)16-21
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume385
Issue number1
DOIs
StatePublished - 17 Jul 2009

Keywords

  • Akt
  • Angiogenesis
  • Benzimidazole
  • HIF-1α inhibitor
  • Hsp90
  • Hypoxia

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