Lithium induces mortality in medulloblastoma cell lines

Abstract

Abstract. Lithium is the main therapeutic agent for the treatment of bipolar disorders but nerve cells are not the sole target of this drug. Indeed, lithium has been reported to target numerous cell types and to affect cell proliferation, differentiation and death. Lithium targets a variety of enzymes among which there is GSK-3ß and a number of cell responses elicited by lithium are mediated by the Wnt pathway that is involved in medulloblastoma (MB) pathogenesis. We studied the in vitro effects of lithium on two different MB cell lines: D283MED and DAOY. High doses of lithium inhibited GSK3-ß, decreased cell proliferation and induced nonapoptotic cell death in both cell lines independently by intracellular levels of ß-catenin that is consistently high only in D283MED. At clinical doses, the anti-neoplastic effects were observed only in this cell line, highlighting the importance of a specific molecular background in determining the target therapy response. In conclusion, lithium could be a promising drug in MB, but an accurate molecular profile predictive of drug response still needs to be clarified.

ALDH2 promotes cancer stemness and metastasis in colorectal cancer through activating β‐catenin signaling

“…Phosphorylation of GSK3β at serine 9 is inhibitory phosphorylation of GSK3β kinase activity and is found to be upregulated once the β-catenin signaling is activated. 57,73 Our results confirm that phospho GSK3β serine 9 and c-Myc protein levels are downregulated in the nucleus after ALDH2 inhibition. However, we found that the total nuclear β-catenin protein level, indicative of Wnt/β-catenin signaling, has not decreased after ALDH2 inhibition by both daidzein and CVT-10216.…”

“…Furthermore, phosphorylation of GSK3β at serine 9 significantly decreased after ALDH2 inhibition by both daidzein and CVT‐10216. Phosphorylation of GSK3β at serine 9 is inhibitory phosphorylation of GSK3β kinase activity and is found to be upregulated once the β‐catenin signaling is activated 57,73 . Our results confirm that phospho GSK3β serine 9 and c‐Myc protein levels are downregulated in the nucleus after ALDH2 inhibition.…”

“…To further confirm how ALDH2 affects c‐Myc expression, we examined the subcellular protein expression level of β‐catenin, pGSK3β serine 9, GSK3β, and c‐Myc. According to the canonical Wnt/β‐catenin pathway, phosphorylation of GSK3β at serine 9 inactivates the kinase activity GSK3β, which would allow the active form of β‐catenin to enter the nucleus 57,58 . So, we treated HCT 116 cells with ALDH2 inhibitors such as CVT‐10216 and daidzein to analyze the protein levels in nuclear and cytosolic fractions by western blot.…”

High Dosage Lithium Treatment Induces DNA Damage and p57Kip2 Decrease

“…Thus, a potential effect on p57 at prolonged lithium therapeutic dosage might not be ruled out. Second, our study employs concentrations of the drug that have been frequently used in investigations evaluating lithium as an anti-proliferative agent in the treatment of numerous cancers, including glioma [44], colorectal cancer [45], medulloblastoma [46], hepatocellular carcinoma [47], and other tumors [48]. Although the dosages employed in these studies were clearly toxic, the development of delivery strategies specifically targeting cancer cells is conceivable.…”