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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