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  • br Brief overview of GSK inhibitors

    2021-11-24


    Brief overview of GSK-3 inhibitors We will briefly summarize some of the key aspects about GSK-3 inhibitors. Additional details of GSK-3 inhibitors in clinical trials have been recently reviewed [5]. GSK-3 is a complicated target as it is involved in many biological processes from neurology, diabetes to cancer. In some circumstances, GSK-3 is considered a tumor suppressor protein while in other cases it is considered a tumor promoter [3]. Many GSK-3 inhibitors have been developed. Long-standing clinical studies have indicated the effects that lithium has on hematopoietic stem Fosaprepitant (HSCs) and other hematopoietic cells [4], [5], [455], [456], [457], [458], [459]. Treatment of patients with lithium resulted in augmentation of the number of circulating HSCs as well as peripheral blood cells [459]. In 1998, it was suggested that lithium treatment might be useful in bone marrow transplantation as it could mobilize HSCs [458]. A target of lithium has been shown to be GSK-3 [460]. The effects of lithium and GSK-3 on hematopoiesis, leukemia and leukemia stem cells have been reviewed recently [4]. Lithium has also been shown to affect other cell types besides hematopoietic cells. Treatment of glioma cells with lithium was determined to suppress cell migration in spheroid cultures by inhibiting GSK-3 activity. In contrast, treatment of these glioma cells with lithium did not extinguish cell viability but did induce alterations in cellular morphologies [461]. The lithium-treated glioma cells displayed retraction of the normally long extensions at their leading edges [290]. Some of the effects of GSK-3 inhibition by lithium and other GSK-3 inhibitors are stimulation of the Wnt/beta-catenin and PI3K/PTEN/Akt/mTORC1 pathways. Suppression of GSK-3 will affect many integral components present in the PI3K/PTEN/Akt/mTORC1 pathway as well as interacting components including: PTEN, mTORC1, TSC1, Rictor, Akt and p70S6K. However, as pointed out in this review, GSK-3 interacts with many other signaling pathways [462], [463]. Thus the effects of inhibiting GSK-3 are predicted to be diverse. Numerous GSK-3 inhibitors have been discovered by basic scientists and pharmaceutical companies [464]. Some studies have suggested that GSK-3 inhibitors may be appropriate for the treatment of certain cancers [465], [466], [467], [468], [469], [470]. The GSK-3 inhibitor SB-415286 induced: cell growth inhibition, cell cycle arrest at G2/M, cyclin B downregulation, beta-catenin stabilization, GSK-3beta S9 phosphorylation and apoptosis in certain leukemia cell lines examined [470]. SB-415286 as well as arsenic trioxide and LiCl inactivated GSK-3beta in certain AML cells by inducing the phosphorylation GSK-3beta at S9 that is associated with its inactivation [471]. In the above-mentioned scenarios, GSK-3 is acting as a tumor promoter and suppression of GSK-3 activity inhibited cell growth. The situation with GSK-3 is complicated as in some cases GSK-3 can act as a tumor suppressor. In this scenario, suppression of GSK-3 would be predicted to promote growth or as we observed induce the chemotherapeutic- and hormonal-based drug resistance of breast cancer cells [6]. Likewise in other studies with breast cancer and medulloblastoma, increased GSK-3 expression was associated with the induction of apoptosis, documenting the tumor suppressor functions of GSK-3 [472], [473]. These tumor suppressor properties of GSK-3 have resulted in caution in terms of the use of GSK-3 inhibitors. As discussed previously, GSK-3 can interact with the TP53 pathway. In some cells, inhibition of TP53 altered the effects of the GSK-3 inhibitors. In contrast, activation of Wnt signaling led to decreased viability through a TP53-independent pathway in these cells [474]. As predicted from the effects that GSK-3 has on Wnt/beta-catenin signaling, suppression of GSK-3 activity by GSK-3 inhibitors can result in activation of beta-catenin. Interestingly, the activation of beta-catenin mediated by GSK-3 inhibitors can augment the cytotoxicity of cisplatin in HEI-OCI cells [475].