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

Tsutomu Anraku,Masayuki Tasaki,Andrew P Mazar,Francis J Giles,Yoshihiko Tomita,Daniel Schmitt,Andrey Ugolkov,Akira Kazama,Hiroo Kuroki,Vladimir Bilim

doi:10.1038/s41598-019-56461-4

Tsutomu Anraku, Masayuki Tasaki + Show 8 more

Open Access

https://doi.org/10.1038/s41598-019-56461-4

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Journal: Scientific Reports	Publication Date: Dec 1, 2019
Citations: 35	License type: open-access

Affiliation: Niigata University, Kameda Medical Center

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.

Highlights

Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, has been identified as a potential therapeutic target in human bladder cancer
We explored the antitumor effects of 9-ING-41, a maleimide-based ATP-competitive small molecule Glycogen synthase kinase-3β (GSK-3β) inhibitor, in bladder cancer cells when combined with an array of potentially active therapeutic agents12. 9-ING-41 is more selective for GSK-3β than for other 320 related kinases when tested in a kinase screen[13]
We tested the GSK-3β inhibitor 9-ING-41, a targeted therapeutic currently being evaluated in a phase 1/2 clinical trial in advanced cancer patients, in bladder cancer cell lines

Summary

Introduction

Glycogen synthase kinase-3 beta (GSK-3β), a serine/threonine kinase, has been identified as a potential therapeutic target in human bladder cancer. 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. Our findings demonstrate that 9-ING-41 enhanced the growth inhibitory effects of gemcitabine or cisplatin when used in combination in bladder cancer cells. We explored the antitumor effects of 9-ING-41, a maleimide-based ATP-competitive small molecule GSK-3β inhibitor, in bladder cancer cells when combined with an array of potentially active therapeutic agents. We demonstrate that treatment with 9-ING-41 enhanced the antitumor effects of chemotherapeutic drugs, and improved the cytotoxic effect of human immune cells in bladder cancer cell lines. We utilized BrdU incorporation assay to confirm that treatment with 9-ING-41

Methods

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Conclusion