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 anti-cancer agents. We synthesized a ureido-calix[8]arene carrying N-acetyl-D-glucosamine (GlcNAc) residues (Compound 1) and previously demonstrated it inhibits C6 glioma cell migration and proliferation, with divergent mechanisms. In the present work we explored in more detail the anti-proliferative 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). Results show that the action of Compound 1 is independent of the GlcNAc residues, requires the presence of multiple ureido groups and does not seem to involve focal adhesion kinase signaling. Inhibition of proliferation is reduced by pre-incubation with EGF and VEGF (20 ng/ml) with Compound 1, and ERK 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.