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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Humans
  • Indoles / administration & dosage
  • Indoles / pharmacology*
  • Irinotecan / administration & dosage
  • Irinotecan / pharmacology
  • Maleimides / administration & dosage
  • Maleimides / pharmacology*
  • Mice
  • Mice, Nude
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / enzymology
  • Neuroblastoma / pathology
  • Xenograft Model Antitumor Assays

Substances

  • 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-(1,3)dioxolo(4,5-f)indol-7-yl)-pyrrole-2,5-dione
  • Enzyme Inhibitors
  • Indoles
  • Maleimides
  • Irinotecan
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta