Lithium increases expression of p21WAF/Cip1 and survivin in human glioblastoma cells

Abstract

Lithium is the most widely prescribed mood stabilizer, but the precise molecular mechanisms underlying its therapeutic function are not yet fully elucidated. Recent preclinical and clinical evidence indicates its neuroprotective and neurotrophic effects. As a tight coupling of function and metabolism in the central nervous system between glial cells and neurons has recently been detected, lithium's effect on glial cells may participate also in the total beneficial effects of this drug. The aim of the present study was to analyze molecular mechanisms induced in human glioblastoma A1235 cells by the treatment with lithium, especially its influence on the expression of apoptosis-related genes. Lower levels of lithium (0.5 mmol/L and 2 mmol/L) did not cause any cytotoxicity or changes in the cell cycle phase distribution following 72 h incubation. However, a higher dose (20 mmol/L) was cytostatic for glioblastoma cells, and caused accumulation of cells in G(2)/M phase of the cell cycle. The treatment with lithium did not alter the levels of Bcl-2 or procaspase-3 and did not cleave PARP, but increased the levels of p21(WAF/Cip1) and survivin. Thus, increased expression of p21(WAF/Cip1) (a protein with antiapoptotic function), and survivin (a protein that supports the growth of cells by suppression of apoptosis and promotion of cell proliferation) may be the early events in the long-term cell response to lithium that are involved in the beneficial effects of this drug.

Down‐regulation of NR4A1 in follicular thyroid carcinomas is restored following lithium treatment

“…Increased concentration of lithium significantly reduced growth of TT cells in a dose dependent fashion 48 . Inhibition of GSK3β by specific inhibitors has shown to reduce tumours growth in other cancers including colon, melanoma and glioblastoma 49–51 . Therefore, these conflicting results could be explained not only for the different concentrations used but also by the fact that the effect of lithium may not be general but cell type specific.…”

Lithium induces mortality in medulloblastoma cell lines

“…However, a multiplicity of cell responses is elicited by lithium outside the nervous system and has profound effects on a variety of processes, including metabolism, cell proliferation and development (2,3). In particular, lithium is described as an inhibitor of the cell cycle (4)(5)(6)(7) and an accelerator of cell death (8)(9)(10). Although some of these data may be debatable, the idea is thus raised that lithium may have antitumor properties.…”

A molecular study of pathways involved in the inhibition of cell proliferation in neuroblastoma B65 cells by the GSK‐3 inhibitors lithium and SB‐415286

“…Although it is effective in clinical studies, this drug is not a selective GSK‐3 inhibitor. Lithium affects more than one target in apoptotic proteins such as Bcl‐2, p53, protein kinase C and others [15–18]. Moreover, apart from lithium, more specific GSK‐3 inhibitors have been developed, among them SB‐415286 which is a potent and selective small‐molecule inhibitor of GSK‐3.…”

“…Although it is effective in clinical studies, this drug is not a selective GSK-3 inhibitor. Lithium affects more than one target in apoptotic proteins such as Bcl-2, p53, protein kinase C and others [15][16][17][18]. Moreover, apart from lithium, more specific GSK-3 inhibitors have been developed, among them SB-415286 which is a potent and selective small-molecule inhibitor of In contrast to the extensive research on lithium, few studies have been performed with SB-415286, a compound that may be a useful tool by which the role of GSK-3 in cellular signalling can be further elucidated.…”