9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer
Hiroo Kuroki, Tsutomu Anraku, Akira Kazama, Vladimir Bilim, Masayuki Tasaki, Daniel Schmitt, Andrew P Mazar, Francis J Giles, Andrey Ugolkov, Yoshihiko Tomita, Hiroo Kuroki, Tsutomu Anraku, Akira Kazama, Vladimir Bilim, Masayuki Tasaki, Daniel Schmitt, Andrew P Mazar, Francis J Giles, Andrey Ugolkov, Yoshihiko Tomita
Abstract
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.
Conflict of interest statement
9-ING-41 has been licensed to Actuate Therapeutics, Inc. Andrew Mazar and Andrey Ugolkov hold an equity interest in Actuate Therapeutics, Inc. Daniel Schmitt and Francis Giles are employees of, and hold an equity interest in, Actuate Therapeutics, Inc. Hiroo Kuroki, Tsutomu Anraku, Akira Kazama, Vladimir Bilim, Masayuki Tasaki and Yoshihiko Tomita declare no competing interests.
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References
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