title: Artesunate as an Anti-Cancer Agent Targets Stat-3 and Favorably Suppresses Hepatocellular Carcinoma.
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.
  
  
  CONCLUSIONS
  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.
authors.forename: M
authors.initials: M
authors.lastname: Ilamathi
authors.forename: S
authors.initials: S
authors.lastname: Santhosh
authors.affiliation: Department of Bioinformatics, CTOR Lab, School of Chemical and Biotechnology, SASTRA University, Thirumalaisamudram, Thanjavur-613401, Tamilnadu, India. sivaramakrishnan@scbt.sastra.edu.
authors.forename: V
authors.initials: V
authors.lastname: Sivaramakrishnan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D019281:Dimerization; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D062105:Molecular Docking Simulation; D050796:STAT3 Transcription Factor / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077332:Artesunate