9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma

Andrey V. Ugolkov, Gennadiy I. Bondarenko, Oleksii Dubrovskyi, Ana P. Berbegall, Samuel Navarro, Rosa Noguera, Thomas V. O'Halloran, Mary J C Hendrix, Francis Joseph Giles, Andrew P Mazar*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK- 3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.

Original languageEnglish (US)
Pages (from-to)717-724
Number of pages8
JournalAnti-Cancer Drugs
Volume29
Issue number8
DOIs
StatePublished - Sep 1 2018

Keywords

  • 9-ING-41
  • CPT-11
  • Chemoresistance
  • Glycogen synthase kinase-3
  • Glycogen synthase kinase-3ß
  • Irinotecan
  • Neuroblastoma

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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    Ugolkov, A. V., Bondarenko, G. I., Dubrovskyi, O., Berbegall, A. P., Navarro, S., Noguera, R., O'Halloran, T. V., Hendrix, M. J. C., Giles, F. J., & Mazar, A. P. (2018). 9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma. Anti-Cancer Drugs, 29(8), 717-724. https://doi.org/10.1097/CAD.0000000000000652