Modulation of C6 Glioma Cell Proliferation by Ureido-Calix[8]arenes

Calixarenes are synthetic macrocyclic compounds that may serve as scaffolds for biologically active molecules and have been proposed as potential anticancer agents. We synthesized a ureido-calix[8]arene carrying N-acetyl-D-glucosamine residue (compound 1) and had previously demonstrated that it inhibits C6 glioma cell migration and proliferation, with divergent mechanisms. In the present work we explored in more detail the antiproliferative effect of compound 1, comparing it to related compounds lacking either the sugar moieties (compound 2), the multiple ureido groups (compound 3) or both (compound 4). The results show that the action of compound 1 is independent of the N-acetyl-D-glucosamine residues, requires the presence of multiple ureido groups and does not seem to involve focal adhesion kinase signaling. Inhibition of proliferation is reduced by preincubation with epidermal growth factor (EGF) and vascular endothelial growth factor (20 ng/ml) with compound 1, and extracellular-related kinase phosphorylation is reduced by treatment with compound 1 in both basal and EGF-stimulated conditions, suggesting that the observed effect depends on a direct interference with growth factor signaling.