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

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-1alpha 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-1alpha through the Hsp90-Akt pathway, leading to the degradation of HIF-1alpha. 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-1alpha via the Hsp90-Akt pathway, and that it can be used as a new lead in developing anticancer drugs.

• Authors: 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
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 385 Issue 1 Pg. 16-21 (Jul 17 2009) ISSN: 1090-2104 [Electronic] United States
• PMID: 19433063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AC1 004
• Antineoplastic Agents
• Benzimidazoles
• HSP90 Heat-Shock Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Proto-Oncogene Proteins c-akt
• Adamantane

Topics

• Adamantane (analogs & derivatives, chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Benzimidazoles (chemistry, pharmacology)
• Cell Line, Tumor
• Drug Design
• HSP90 Heat-Shock Proteins (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)