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6-Bromoindirubin-3'-oxime inhibits JAK/STAT3 signaling and induces apoptosis of human melanoma cells.

Abstract
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.
AuthorsLucy Liu, Sangkil Nam, Yan Tian, Fan Yang, Jun Wu, Yan Wang, Anna Scuto, Panos Polychronopoulos, Prokopios Magiatis, Leandros Skaltsounis, Richard Jove
JournalCancer research (Cancer Res) Vol. 71 Issue 11 Pg. 3972-9 (Jun 01 2011) ISSN: 1538-7445 [Electronic] United States
PMID21610112 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • 6-bromoindirubin-3'-oxime
  • Indoles
  • Oximes
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Janus Kinases
Topics
  • Animals
  • Apoptosis (drug effects, physiology)
  • Cell Growth Processes (drug effects)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Female
  • Humans
  • Indoles (pharmacology)
  • Janus Kinases (antagonists & inhibitors, metabolism)
  • Melanoma (drug therapy, metabolism, pathology)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Oximes (pharmacology)
  • Phosphorylation (drug effects)
  • STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
  • Signal Transduction (drug effects)
  • Xenograft Model Antitumor Assays

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