Survivin-targeted drug screening platform identifies a matrine derivative WM-127 as a potential therapeutics against hepatocellular carcinoma. (1st July 2018)

• Record Type: Journal Article
• Authors: Yin, Haisen; Que, Risheng; Liu, Chunying; Ji, Weidan; Sun, Bin; Lin, Xuejing; Zhang, Qin; Zhao, Xinying; Peng, Zhangxiao; Zhang, Xiaofeng; Qian, Haihua; Chen, Lei; Yao, Yonggang; Su, Changqing
• Is Part Of: Cancer letters. Volume 425(2018)
• Page Start: 54
• Page End: 64
• Publication Date: 2018-07-01
• Subjects: Hepatocellular carcinoma -- Drug screening -- Survivin -- Matrine derivative -- Enhanced green fluorescent protein; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.03.044
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death which needs novel drugs to improve patient outcome. Survivin overexpresses in HCC and contributes to HCC malignant progression. In this study, we established a Survivin-targeted drug screening platform, a cell model HepG2-Sur5P-EGFP-Sur3U stably transfected with lentivirus carrying an EGFP expression cassette, in which the EGFP expression was regulated by the upstream Survivin promoter and downstream Survivin 3′-UTR. By using this platform, we screened and easily identified one of matrine derivatives, WM-127, from hundreds of matrine derivatives. WM-127 was demonstrated to be a strong Survivin inhibitor that inhibited cell proliferation, induced cell cycle arrest and apoptosis of HCC cells, and suppressed the growth of HCC xenografted tumors in nude mice, suggesting that WM-127 might be a promising drug for HCC treatment. WM-127 exhibited less cytotoxicity in normal cells. Mechanistic studies showed that WM-127 suppressed the activity of Survivin/β-catenin pathway and the expression of Bax to induce cell cycle arrest and apoptosis. Taken together, we constructed an economical, practical, efficient and convenient cell platform for screening the Survivin-targeted drugs from the enormous diversity of chemicals or factors, which would be a potential tool for antitumor drug research and development. Highlights: A Survivin-targeted antitumor drug screening cell model was established. A matrine derivative, WM-127, was identified from hundreds of matrine derivatives by using this model. WM-127 was demonstrated to be a strong Survivin inhibitor that could suppress HCC cell malignant behaviors and tumor growth. The cell model would be a potential tool for antitumor drug research and development.