Journal
ANTI-CANCER DRUGS
Volume 29, Issue 8, Pages 717-724Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0000000000000652
Keywords
9-ING-41; chemoresistance; CPT-11; glycogen synthase kinase-3; glycogen synthase kinase-3; irinotecan; neuroblastoma
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Funding
- Cancer Center Support Grant [2 P30 CA060553-19]
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
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Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3 (GSK-3) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK-3 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-3 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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