Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells

Molecular Cancer

Research

Wendan Yu¹  Zhenlong Yu¹  Peipei Dong¹  Chao Wang¹  Baojing Zhang¹  Canhui Yi¹  Wei Guo¹  Xiuli Wang¹  Xiaokui Huo¹  Yao Xiao¹  Lin Huang¹  Wenjing Yang¹  Yu Qin¹  Songshu Meng¹  Xiaochi Ma¹  Yuhui Yuan¹  Quentin Liu²  Wuguo Deng² 

[1] Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, 116044, Dalian, China;Institute of Cancer Stem Cell; College of Pharmacy, Dalian Medical University, Lvshun South Road No 9, 116044, Dalian, China;Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Canter of Cancer Medicine, Guangzhou, China;

关键词: Gamabufotalin;    NSCLC;    COX-2;    NF-κB;    p300;    IKKβ;   

DOI  :  10.1186/1476-4598-13-203

 received in 2014-05-06, accepted in 2014-08-25,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundGamabufotalin (CS-6), a major bufadienolide of Chansu, has been used for cancer therapy due to its desirable metabolic stability and less adverse effect. However, the underlying mechanism of CS-6 involved in anti-tumor activity remains poorly understood.MethodsThe biological functions of gamabufotalin (CS-6) were investigated by migration, colony formation and apoptosis assays in NSCLC cells. The nuclear localization and interaction between transcriptional co-activator p300 and NF-κB p50/p65 and their binding to COX-2 promoter were analyzed after treatment with CS-6. Molecular docking study was used to simulate the interaction of CS-6 with IKKβ. The in vivo anti-tumor efficacy of CS-6 was also analyzed in xenografts nude mice. Western blot was used to detect the protein expression level.ResultsGamabufotalin (CS-6) strongly suppressed COX-2 expression by inhibiting the phosphorylation of IKKβ via targeting the ATP-binding site, thereby abrogating NF-κB binding and p300 recruitment to COX-2 promoter. In addition, CS-6 induced apoptosis by activating the cytochrome c and caspase-dependent apoptotic pathway. Moreover, CS-6 markedly down-regulated the protein levels of COX-2 and phosphorylated p65 NF-κB in tumor tissues of the xenograft mice, and inhibited tumor weight and size.ConclusionsOur study provides pharmacological evidence that CS-6 exhibits potential use in the treatment of COX-2-mediated diseases such as lung cancer.

【 授权许可】

Unknown   
© Yu et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.