Clinically relevant GSK-3[beta] inhibitor 9-ING-41 is active as a single agent and in combination with other antitumor therapies in human renal cancer

Glycogen synthase kinase-3 (GSK-3), a serine/threonine kinase, is involved in a broad range of pathological processes including cancer. GSK-3 has two isoforms, GSK-3[alpha] and GSK-3[beta], and GSK-3[beta] has been recognized as a therapeutic target for the development of new anticancer drugs. The present study aimed to investigate the antitumor effects of 9-ING-41, which is a maleimide-based ATP-competitive small molecule GSK-3[beta] inhibitor active in patients with advanced cancer. In renal cancer cell lines, treatment with 9-ING-41 alone induced cell cycle arrest and apoptosis, and autophagy inhibitors increased the antitumor effects of 9-ING-41 when used in combination. Treatment with 9-ING-41 potentiated the antitumor effects of targeted therapeutics and increased the cytotoxic effects of cytokine-activated immune cells on renal cancer cell lines. These results provided a compelling rationale for the inclusion of patients with renal cancer in studies of 9-ING-41, both as a single agent and in combination with current standard therapies. Key words: glycogen synthase kinase-3, renal cell carcinoma, apoptosis, cell cycle arrest, immune cells