A Synthetic Glycosphingolipid-Induced Antiproliferative Effect in Melanoma Cells Is Associated with Suppression of FAK, Akt, and Erk Activation(Medicinal Chemistry)

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Numerous studies have demonstrated the participation of glicolipids in signal transduction and the regulation of melanoma cell growth and apoptosis. Hoping to discover new anticancer drugs, we have synthesized ten glycolipids found in various invertebrates that do not have sialic acids. These compounds were tested for antiproliferative effects on a melanoma cell line, B16F10. A synthetic compound, Manβ(1-4)[Fucα(1-3)]Glcβ1-Cer, (glycosphingolipid 7), which was identified in the millipede Parafontaria laminata armigera, had an antiproliferative effect on the melanoma cells. This compound suppressed the activation of the focal adhesion kinase (FAK)-Akt pathway as well as the activation of extracellular signal-regulated kinase (Erk)1/2 pathway involved in cell proliferation. Expression of the cell cycle proteins, cyclin Dl and CDK4, was suppressed by glycosphingolipid 7. From these results, glycosphingolipid 7 suppressed the activation of the FAK-Akt pathway and of Erk1/2, which resulted in a decrease in the expression of cyclin D1 and CDK4. Glycosphingolipid 7 might be a candidate for an inhibitor of cell proliferation in melanomas.
2008-06-01