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

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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 p21Cip1/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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Acknowledgments

This work was supported by a grant from the CERN Foundation (to H.C. and W.P.) and from Moleculin, LLC (to W.P.).

Conflict of interest

Dr. Waldemar Priebe is the lead inventor in the patent disclosing WP1193 and related analogs, and has a financial interest Moleculin, LLC, the company that licensed this patent. Timothy Madden and Charles Conrad are listed as inventors on the patent disclosing WP1193 and related analogs, and have a financial interest Moleculin, LLC, the company that licensed this patent.

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Authors and Affiliations

  1. Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Ke Sai, Shuzhen Wang, Veerakumar Balasubramaniyan, Charles Conrad, Atreyi Dasgupta, Su Guan, W. K. Alfred Yung & Howard Colman

  2. Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Kenneth Aldape

  3. Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Frederick F. Lang

  4. Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Slawomir Szymanski, Izabela Fokt, Timothy Madden & Waldemar Priebe

  5. 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

    Ke Sai & Zhongping Chen

  6. Department of Neurosurgery and Huntsman Cancer Institute, University of Utah, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA

    Howard Colman

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  1. Ke Sai
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Correspondence to Howard Colman.

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Sai, K., Wang, S., Balasubramaniyan, V. et al. Induction of cell-cycle arrest and apoptosis in glioblastoma stem-like cells by WP1193, a novel small molecule inhibitor of the JAK2/STAT3 pathway. J Neurooncol 107, 487–501 (2012). https://doi.org/10.1007/s11060-011-0786-z

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