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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

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

Javier G Pizarro, Jaume Folch, José Luis Esparza, J Jordan, Mercè Pallàs, Antoni Camins

J Cell Mol Med. 2009 Sep;13(9B):3906-17.

PMID: 18624766

Abstract:

Pharmacological GSK-3 inhibitors are potential drugs for the treatment of neurodegenerative diseases, cancer and diabetes. We examined the antiproliferative effects of two GSK-3 inhibitors, lithium and SB-415286, on B65 neuroblastoma cell line. Treatment of B65 cells with either drug administered separately caused a decrease in cell proliferation that was associated with G(2)/M cell cycle arrest. Cell-cycle proteins such as cyclins D, E, A, cdk4 and cdk2 were up-regulated. Since lithium and SB-415286-induced G(2)/M arrest we studied changes in the expression of proteins involved in this phase, specifically cyclin B, cdc2 and the phosphorylated form of this protein (tyr15-cdc2). Both drugs increased the expression of tyr15-cdc2, thus inhibiting mitosis. On the other hand, SB-415286 increased the expression of SIRT2, involved in the regulation of proliferation. Moreover, cell-cycle arrest mediated by SB-415286 was accompanied by apoptosis that was not prevented by 100 microM of zVAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone), a pan-caspase inhibitor. Likewise, GSK-3 inhibitors did not affect the mitochondrial release of apoptosis inducing factor (AIF). We conclude that inhibitors of GSK-3 induced cell-cycle arrest, mediated by the phosphorylation of cdc2 and, in the case of SB-415286, SIRT2 expression, which induced apoptosis in a caspase-independent manner.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP264218237	SB 415286		264218-23-7	Price

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