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.
- Content Type Journal Article
- Category Laboratory Investigation
- Pages 1-15
- DOI 10.1007/s11060-011-0786-z
- Authors
- Ke Sai, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Shuzhen Wang, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Veerakumar Balasubramaniyan, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Charles Conrad, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Frederick F. Lang, Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Kenneth Aldape, Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Slawomir Szymanski, Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Izabela Fokt, Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Atreyi Dasgupta, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Timothy Madden, Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Su Guan, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Zhongping Chen, Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
- W. K. Alfred Yung, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Waldemar Priebe, Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Howard Colman, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Journal Journal of Neuro-Oncology
- Online ISSN 1573-7373
- Print ISSN 0167-594X
Sent with MobileRSS for iPhone
No comments:
Post a Comment