https://scholars.lib.ntu.edu.tw/handle/123456789/568446
Title: | SC-60, a dimer-based sorafenib derivative, shows a better anti-hepatocellular carcinoma effect than sorafenib in a preclinical hepatocellular carcinoma model | Authors: | Tai W.-T. Shiau C.-W. Li Y.-S. Chen Y.-L. Chu P.-Y. Huang J.-W. Hsu C.-Y. Hsu Y.-C. PEI-JER CHEN Chen K.-F. |
Issue Date: | 2014 | Journal Volume: | 13 | Journal Issue: | 1 | Start page/Pages: | 27-36 | Source: | Molecular Cancer Therapeutics | Abstract: | Sorafenib is the first approved targeted therapeutic reagent for hepatocellular carcinoma. Here, we report that SC-60, a dimer-based sorafenib derivative, overcomes the resistance of sorafenib and shows a better anti-hepatocellular carcinoma effect in vitro and in vivo. SC-60 substantially increased SH2 domaincontaining phosphatase 1 (SHP-1) phosphatase activity in hepatocellular carcinoma cells and purified SHP- 1 proteins, suggesting that SC-60 affects SHP-1 directly. Molecular docking and truncated mutants of SHP- 1 further confirmed that SC-60 interferes with the inhibitory N-SH2 domain to relieve the closed catalytic protein tyrosine phosphatase domain of SHP-1. Deletion of N-SH2 domain (dN1) or pointmutation (D61A) of SHP-1 abolished the effect of SC-60 on SHP-1, p-STAT3, and apoptosis. Importantly, SC-60 exhibited significant survival benefits compared with sorafenib in a hepatocellular carcinoma orthotopic model via targeting the SHP-1/STAT3-related signaling pathway. In summary, dimer derivative of sorafenib, SC-60, is a SHP-1 agonist and may be a potent reagent for hepatocellular carcinoma-targeted therapy. ? 2013 American Association for Cancer Research. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84892616236&doi=10.1158%2f1535-7163.MCT-13-0595&partnerID=40&md5=bacfbe96ef7390f1b5020716de7525d3 https://scholars.lib.ntu.edu.tw/handle/123456789/568446 |
ISSN: | 1535-7163 | DOI: | 10.1158/1535-7163.MCT-13-0595 | SDG/Keyword: | angiogenesis inhibitor; cyclin D1; dimer; protein SH2; protein tyrosine phosphatase SHP 1; sc 60; sorafenib; STAT3 protein; survivin; unclassified drug; animal experiment; animal model; antineoplastic activity; apoptosis; article; binding affinity; cancer inhibition; cancer resistance; cancer survival; cell viability; controlled study; drug cytotoxicity; drug dose escalation; enzyme activity; human; human cell; immunoprecipitation; liver cell carcinoma; molecular docking; molecular model; mouse; nonhuman; point mutation; priority journal; structure activity relation; tumor xenograft; Apoptosis; Carcinoma, Hepatocellular; Catalytic Domain; Cell Line, Tumor; Humans; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Point Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Signal Transduction; STAT3 Transcription Factor; Xenograft Model Antitumor Assays |
Appears in Collections: | 臨床醫學研究所 |
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