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Journal of Neuro-Oncology
Published in: Journal of Neuro-Oncology 3/2012

01-05-2012 | Laboratory Investigation

Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway

Authors: Ke Sai, Shuzhen Wang, Veerakumar Balasubramaniyan, Charles Conrad, Frederick F. Lang, Kenneth Aldape, Slawomir Szymanski, Izabela Fokt, Atreyi Dasgupta, Timothy Madden, Su Guan, Zhongping Chen, W. K. Alfred Yung, Waldemar Priebe, Howard Colman

Published in: Journal of Neuro-Oncology | Issue 3/2012

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Abstract

Glioma stem-like cells (GSCs) may be the initiating cells in glioblastoma (GBM) and contribute to the resistance of these tumors to conventional therapies. Development of novel chemotherapeutic agents and treatment approaches against GBM, especially those specifically targeting GSCs are thus necessary. In the present study, we found that a novel Janus kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway inhibitor (WP1193) significantly decreased the proliferation of established glioma cell lines in vitro and inhibit the growth of glioma in vivo. To test the efficacy of WP1193 against GSCs, we then administrated WP1193 to GSCs isolated and expanded from multiple human GBM tumors. We revealed that WP1193 suppressed phosphorylation of JAK2 and STAT3 with high potency and demonstrated a dose-dependent inhibition of proliferation and neurosphere formation of GSCs. These effects were at least due in part to G1 arrest associated with down-regulation of cyclin D1 and up-regulation of p21 Cip1/Waf-1 . Furthermore, WP1193 exposure decreased expression of stem cell markers including CD133 and c-myc, and induced cell death in GSCs through apoptosis. Taken together, our data indicate that WP1193 is a potent small molecule inhibitor of the JAK2/STAT3 pathway that shows promise as a therapeutic agent against GBM by targeting GSCs.
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Metadata
Title
Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway
Authors
Ke Sai
Shuzhen Wang
Veerakumar Balasubramaniyan
Charles Conrad
Frederick F. Lang
Kenneth Aldape
Slawomir Szymanski
Izabela Fokt
Atreyi Dasgupta
Timothy Madden
Su Guan
Zhongping Chen
W. K. Alfred Yung
Waldemar Priebe
Howard Colman
Publication date
01-05-2012
Publisher
Springer US
Published in
Journal of Neuro-Oncology / Issue 3/2012
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI
https://doi.org/10.1007/s11060-011-0786-z

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