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

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.

• 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
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 107 Issue 3 Pg. 487-501 (May 2012) ISSN: 1573-7373 [Electronic] United States
• PMID: 22249692 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyanoacrylates
• Pyridines
• STAT3 Transcription Factor
• WP 1193
• Janus Kinase 2

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Cycle Checkpoints (drug effects)
• Cyanoacrylates (pharmacology)
• Flow Cytometry
• Glioblastoma (drug therapy, metabolism)
• Humans
• Janus Kinase 2 (metabolism)
• Male
• Mice
• Mice, Nude
• Neoplastic Stem Cells (drug effects, metabolism)
• Pyridines (pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays