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

  • Anticancer Drugs. 2018 Sep;29(8):717-724. doi: 10.1097/CAD.0000000000000652.
Andrey V Ugolkov  1  2 ,  Gennadiy I Bondarenko  2 ,  Oleksii Dubrovskyi  2 ,  Ana P Berbegall  3  4 ,  Samuel Navarro  3  4 ,  Rosa Noguera  3  4 ,  Thomas V O'Halloran  5  2 ,  Mary J Hendrix  5 ,  Francis J Giles  1  5 ,  Andrew P Mazar  6  5  2
Affiliations
  • 1. Department of Medicine, Developmental Therapeutic Program, Division of Hematology/Oncology.
  • 2. Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois.
  • 3. Department of Pathology, Medical School, University of Valencia-INCLIVA, Valencia.
  • 4. Cancer CIBER (CIBERONC), Madrid, Spain.
  • 5. Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.
  • 6. Department of Pharmacology, Feinberg School of Medicine, Northwestern University.
PMID: 29846250 DOI: 10.1097/CAD.0000000000000652
Abstract

Advanced stage neuroblastoma is a very aggressive pediatric Cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3β (GSK-3β) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3β 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-3β 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.

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