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 language | English |
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Pages (from-to) | 16-21 |
Number of pages | 6 |
Journal | Biochemical and Biophysical Research Communications |
Volume | 385 |
Issue number | 1 |
DOIs | |
State | Published - 17 Jul 2009 |
Keywords
- Akt
- Angiogenesis
- Benzimidazole
- HIF-1α inhibitor
- Hsp90
- Hypoxia