Abstract 764: 6-Bromoindirubin-3′-oxime induces apoptosis of human melanoma cells associated with inhibition of JAK/STAT3 signaling

Abstract

Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated in many diverse human tumors and contributes to malignant progression in part by preventing apoptosis. Janus kinases (JAKs), which are receptor-associated tyrosine kinases, phosphorylate STAT3 in normal as well as tumor cells in response to stimulation with cytokines or growth factors. Thus, the JAK/STAT3 signaling pathway has emerged as a promising new target for development of anti-cancer therapeutics. Previous studies demonstrated that bromoindirubin derivatives have anti-cancer activity with enhanced solubility and bioavailability compared to indirubin, which is a natural product with anti-tumor activity found in traditional herbal medicines. The marine natural product derivative 6-bromoindirubin-3′-oxime (6-BIO) has been shown to inhibit kinase activity of cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3β (GSK-3β). Here, we report that 6-BIO induces apoptosis of A2058 melanoma cells, associated with inhibition of JAK/STAT3 signaling. Our data show that 6-BIO inhibits viability and induces apoptosis of melanoma cells with an IC50 value of 5 µM, consistent with reduction of phosphorylation of JAK family kinases (JAK1, JAK2 and TYK2) and STAT3 in both dose- and time-dependent manners. Expression of STAT3 downstream targets involved in preventing apoptosis, particularly Mcl-1, was decreased through inactivation of STAT3 by 6-BIO at similar IC50 values. 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 the cells treated with 6-BIO. Taken together, these data demonstrate that JAK/STAT3 signaling was selectively inhibited by 6-BIO associated with induction of tumor cell apoptosis. Our findings support further development of 6-BIO as a potential anti-cancer therapeutic agent that targets JAK/STAT3 signaling in tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 764.