Artesunate as an Anti-Cancer Agent Targets Stat-3 and Favorably Suppresses Hepatocellular Carcinoma

Author(s): M. Ilamathi, S. Santhosh, V. Sivaramakrishnan

Journal Name: Current Topics in Medicinal Chemistry

Volume 16 , Issue 22 , 2016

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Graphical Abstract:


Background: Aberrant signal transducer and activator of transcription 3 (STAT-3) molecular signaling elicit hepatocellular carcinoma (HCC) in humans. Therefore, targeting STAT-3 is considered as an attractive option towards suppression of HCC in humans. Objective: Our objective is to identify a potential small molecule inhibitor that can specifically target STAT-3 and suppress HCC. Methods: In this study, we analyze a group of sesquiterpene lactone (STL) candidates that has been recently reported in preclinical trials against cancer by a unified computational and experimental approach. Results: Our virtual analysis of the STL candidates revealed Artesunate (ATS) as the best potential inhibitor of STAT-3 with comparable potency to specific inhibitor S3I-201. We also observed that ATS inhibited IL-6 driven STAT-3-DNA binding activity with comparable potency to S3I-201 in a cell free system. Furthermore ATS was observed to interfere with STAT-3 dimerization and suppression of both constitutive and IL-6 inducible STAT-3 in vitro. Nevertheless, we also observed that ATS modulated STAT-3 dependent targets (procaspase-3, Bcl-xl and survivin) favoring occurrence of apoptosis in vitro. Overall, the putative inhibition of STAT-3 by ATS suggested its capacity to interfere with STAT-3 dimerization by binding to the SH2 domain of STAT-3 monomer. It resulted in suppression of STAT-3 and also favored promotion of in vitro cells towards apoptosis. Consequently, ATS also exhibited selective cytotoxicity of cancer cells over normal cells in vitro. Conclusion: All the above observations substantiated by unified computational and in vitro experimental approaches suggested its potential role as a therapeutic anti-cancer agent against HCC.

Keywords: Signal transducer and activator of transcription, Artesunate, Anti-cancer, Sesquiterpene Lactone, Free energy binding, SH2 domain, Small molecule inhibitor.

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Article Details

Year: 2016
Page: [2453 - 2463]
Pages: 11
DOI: 10.2174/1568026616666160212122820
Price: $65

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