期刊论文详细信息
Molecular Cancer
Synthesis, characterization, and evaluation of a novel inhibitor of WNT/β-catenin signaling pathway
Research
Jian Sun1  Wenting Chen1  Jinghui Wang1  Guang Yang1  Yihui Chen1  Yuheng Deng2  Zhongling Zhu3  Zhao Yan3 
[1] Beijing Laviana Pharmatech Co., Ltd, 102206, Beijing, P. R. China;Department of Chemistry, Capital Normal University, 100048, Beijing, P. R. China;Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, 300060, Tianjin, P. R. China;Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, P. R. China;
关键词: β-catenin;    Cell proliferation;    Inhibitor;    Tumorigenesis;    Wnt signaling pathway;   
DOI  :  10.1186/1476-4598-12-116
 received in 2013-05-22, accepted in 2013-09-18,  发布年份 2013
来源: Springer
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【 摘 要 】

BackgroundWnt/β-catenin signaling is a highly conserved pathway in organism evolution and is important in many biological processes. Overactivation of Wnt/β-catenin signaling is closely related to tumor development and progression. To identify potent small molecules that can fight aberrant Wnt/β-catenin-mediated cancer, we synthesized a novel pyrazoline derivative (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxamide, BHX) to block Wnt signaling, and determined the absolute configuration of its precursor (ethyl 1,3,4-triphenyl-4,5-dihydro-1H-pyrazole-5-carboxylate). We then evaluated the inhibitory effect of BHX in vitro and in vivo.ResultsCell proliferation was assessed in three human cancer cell lines (A549, HT29, and MGC803) in the presence and absence of BHX using MTS assays. BHX effectively inhibited A549, HT29, and MGC803 cell proliferation with IC50 of 5.43 ± 1.99, 6.95 ± 0.24, and 7.62 ± 1.31 μM, respectively. BHX significantly induced apoptosis and G1 phase arrest in A549 and MGC803 cells. The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment. The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model. A549 xenograft growth was suppressed by 50.96% in nude mice treated continuously with 100 mg/kg BHX for 21 d. Weight remained almost unchanged, which indicates the low toxicity of the compound.ConclusionsOur data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.

【 授权许可】

CC BY   
© Yan et al.; licensee BioMed Central Ltd. 2013

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