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Title 

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

Authors 

Mi Sun WonN ImS ParkS K BoovanahalliY JinX JinKyung Sook ChungKang Moo rimKiho LeeSong Kyu ParkHwan Mook KimByoung-Mog KwonJung Joon LeeKyeong Lee

Publisher 

Elsevier

Issue Date 

2009

Citation 

Biochemical and Biophysical Research Communications, vol. 385, no. 1, pp. 16-21

Keywords 

AktangiogenesisbenzimidazoleHIF-1α inhibitorHsp90hypoxia

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.

ISSN 

0006-291X

Link 

http://dx.doi.org/10.1016/j.bbrc.2009.05.022

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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