1. 9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma.
- Author
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Ugolkov AV, Bondarenko GI, Dubrovskyi O, Berbegall AP, Navarro S, Noguera R, O'Halloran TV, Hendrix MJ, Giles FJ, and Mazar AP
- Subjects
- Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cell Growth Processes drug effects, Cell Line, Tumor, Drug Synergism, Female, Glycogen Synthase Kinase 3 beta metabolism, Humans, Indoles administration & dosage, Irinotecan administration & dosage, Irinotecan pharmacology, Maleimides administration & dosage, Mice, Mice, Nude, Neuroblastoma enzymology, Neuroblastoma pathology, Xenograft Model Antitumor Assays, Enzyme Inhibitors pharmacology, Glycogen Synthase Kinase 3 beta antagonists & inhibitors, Indoles pharmacology, Maleimides pharmacology, Neuroblastoma drug therapy
- 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.
- Published
- 2018
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