STAT3 is persistently activated and contributes to malignant progression in various
cancers. Janus activated
kinases (JAK) phosphorylate STAT3 in response to stimulation by
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 growth inhibition of human
melanoma cells and assessed 6BIO as a potential anticancer
drug candidate. We found that 6BIO is a pan-
JAK inhibitor that induces 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 dose- and time-dependent manners. Consistent with inhibition of STAT3 signaling, expression of the antiapoptotic
protein Mcl-1 was downregulated. In contrast to the decreased levels of phosphorylation of JAKs and STAT3, phosphorylation levels of the Akt and
mitogen-activated protein kinase (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 show 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 anticancer therapeutic agent that targets JAK/STAT3 signaling in
tumor cells.