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Signal Transducer and Activator of Transcription 3 (STAT3) is persistently activated and contributes to malignant progression in various cancers.Janus kinases (JAKs) phosphorylate STAT3 in response to stimulation with cytokines or growth factors.The STAT3 signaling pathway has been validated as a promising target for development of anticancer therapeutics.Small-molecule inhibitors of JAK/STAT3 signaling represent potential molecular-targeted cancer therapeutic agents.In this study, we investigated the role of JAK/STAT3 signaling in 6-bromoindirubin-3-oxime (6BIO) mediated apoptosis of human melanoma cells.We screened a group of 6-bromoindirubin derivatives for anticancer activity in human cancer cells by using MTS cell viability assay.6BIO was identified as a potent anticancer agent.By conducting apoptosis assay, immunobloting analysis and in vitro kinase assay, we found that 6BIO is a pan-JAK inhibitor that induced apoptosis of human melanoma cells.6BIO directly inhibited JAK family kinase activity both in vitro and in cancer cells.Apoptosis of human melanoma cells induced by 6BIO was associated with reduced phosphorylation of JAKs and STAT3 in both a dose-and time-dependent manner.Consistent with inhibition of STAT3 signaling, the anti-apoptotic protein Mcl-1 was down-regulated.In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the AKT and MAPK signaling proteins were not inhibited in cells treated with 6BIO.Importantly, 6BIO suppressed tumor growth in vivo with low toxicity in a mouse xenograft model of melanoma.Taken together, these results demonstrate that 6BIO is a novel pan-JAK inhibitor that can selectively inhibit STAT3 signaling and induces tumor cell apoptosis.Our findings support further development of 6BIO as a potential anti-cancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells.