9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer

Sci Rep. 2019 Dec 27;9(1):19977. doi: 10.1038/s41598-019-56461-4.


Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, has been identified as a potential therapeutic target in human bladder cancer. In the present study, we investigated the antitumor effect of a small molecule GSK-3β inhibitor, 9-ING-41, currently in clinical studies in patients with advanced cancer, in bladder cancer cell lines. We found that treatment with 9-ING-41 leads to cell cycle arrest, autophagy and apoptosis in bladder cancer cells. The autophagy inhibitor chloroquine potentiated the antitumor effects of 9-ING-41 when tested in combination studies. Our findings also demonstrate that 9-ING-41 enhanced the growth inhibitory effects of gemcitabine or cisplatin when used in combination in bladder cancer cells. Finally, we found that 9-ING-41 sensitized bladder cancer cells to the cytotoxic effects of human immune effector cells. Our results provide a rationale for the inclusion of patients with advanced bladder cancer in clinical studies of 9-ING-41.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Autophagy / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / pharmacology
  • Drug Synergism
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
  • Humans
  • Indoles / pharmacology*
  • Maleimides / pharmacology*
  • Protein Kinase Inhibitors / pharmacology*
  • Urinary Bladder Neoplasms


  • 3-(5-fluorobenzofuran-3-yl)-4-(5-methyl-5H-(1,3)dioxolo(4,5-f)indol-7-yl)-pyrrole-2,5-dione
  • Antineoplastic Agents
  • Indoles
  • Maleimides
  • Protein Kinase Inhibitors
  • Glycogen Synthase Kinase 3 beta
  • Cisplatin