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Journal of Neuro-Oncology

, Volume 107, Issue 3, pp 487–501 | Cite as

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

  • 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 ColmanEmail author
Laboratory Investigation

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.

Keywords

Glioblastoma STAT3 Stem-like cell Targeted therapy Apoptosis 

Notes

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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Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Ke Sai
    • 1
    • 5
  • Shuzhen Wang
    • 1
  • Veerakumar Balasubramaniyan
    • 1
  • Charles Conrad
    • 1
  • Frederick F. Lang
    • 3
  • Kenneth Aldape
    • 2
  • Slawomir Szymanski
    • 4
  • Izabela Fokt
    • 4
  • Atreyi Dasgupta
    • 1
  • Timothy Madden
    • 4
  • Su Guan
    • 1
  • Zhongping Chen
    • 5
  • W. K. Alfred Yung
    • 1
  • Waldemar Priebe
    • 4
  • Howard Colman
    • 1
    • 6
    Email author
  1. 1.Department of Neuro-OncologyUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of PathologyUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of NeurosurgeryUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA
  4. 4.Department of Experimental TherapeuticsUniversity of Texas M.D. Anderson Cancer CenterHoustonUSA
  5. 5.Department of Neurosurgery/Neuro-Oncology, State Key Laboratory of Oncology in Southern ChinaSun Yat-Sen University Cancer CenterGuangzhouPeople’s Republic of China
  6. 6.Department of Neurosurgery and Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUSA

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