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

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.