Janus activated kinase 2/signal transducer and activator of transcription 3 pathway mediates icariside II-induced apoptosis in U266 multiple myeloma cells.

Abstract

Although the flavonoid icariside II exhibits anti-inflammatory and anti-cancer activities, its molecular targets/pathways in human multiple myeloma cells are poorly understood. To analyze the effects on signal transducer and activator of transcription 3 (STAT3) signaling and apoptosis, U266 multiple myeloma cells were treated with icariside II and performed Western blotting, electrophoretic mobility gel shift assay (EMSA), RT-PCR, proliferation assay, cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Icariside II inhibited STAT3 activation and enhanced the expression of SHP-1 and PTEN through inhibiting Janus activated kinase 2 (JAK2) and c-Src. Icariside II down-regulated the expression of STAT3 target genes Bcl-2, Bcl-x(L), survivin, cyclin D(1), COX-2 and vascular endothelial growth factor (VEGF). Also, icariside II enhanced poly (ADP-ribose) polymerase (PARP) cleavage and caspase-3 activation. Pervanadate reversed the icariside II-mediated STAT3 inactivation and also blocked the cleavages of caspase-3 and PARP, suggesting involvement of STAT3 pathway in icariside II-induced apoptosis. Furthermore, icariside II enhanced the apoptotic effects of clinically used drugs thalidomide and bortezomib in U266 cells. Icariside II could be a potential therapeutic intervention agent alone or in combination with current drugs for multiple myeloma as a novel blocker of STAT3 signaling cascades at multiple levels, contributing to its anti-proliferative and anti-apoptosis.

• Authors: Sun-Hee Kim, Kwang Seok Ahn, Soo-Jin Jeong, Tae-Rin Kwon, Ji Hoon Jung, Sun-Mi Yun, Ihn Han, Seok-Geun Lee, Dae Keun Kim, Minkyung Kang, Chang-Yan Chen, Jung Weon Lee, Sung-Hoon Kim
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 654 Issue 1 Pg. 10-6 (Mar 01 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21172343 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier B.V. All rights reserved.

Chemical References

• Boronic Acids
• Flavonoids
• Pyrazines
• STAT3 Transcription Factor
• STAT3 protein, human
• baohuoside I
• Thalidomide
• Bortezomib
• JAK2 protein, human
• Janus Kinase 2

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Boronic Acids (administration & dosage)
• Bortezomib
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Flavonoids (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Multiple Myeloma (drug therapy, pathology)
• Pyrazines (administration & dosage)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Thalidomide (administration & dosage)