calixarenes and Glioma

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.

Topics: Acetylglucosamine; Animals; Antineoplastic Agents; Calixarenes; Cell Division; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epidermal Growth Factor; Focal Adhesion Kinase 1; Glioma; Phosphorylation; Rats; Signal Transduction; Vascular Endothelial Growth Factor A

Beta1,4-Galactosyltransferases (beta1,4-GalTase) exposed on the cell surface are involved in cell migration. Specifically, beta1,4-GalTase V is highly expressed in glioma and promotes invasion, growth, and survival of glioma cells. A glycocalix[8]arene exposing N-acetylglucosamine (GlcNAc) residues (compound 1) inhibited rat C6 glioma cell migration as assessed in a scratch wound model. This effect was related to inhibition of focal adhesion kinase phosphorylation, measured by western blot analysis, and specifically observed in the area bordering the scratch wound. Compound 1 inhibited also C6 cell proliferation, an effect unrelated to its ability to interact with GalTase as it was mimicked by different calix[8]arene derivatives, all characterized by multivalency and ureido groups. Compound 1 did not induce apoptotic death, but caused a different distribution of C6 cells within the cell cycle. The results here reported identify compound 1 as a molecule able to exert inhibitory effects on C6 cell migration and proliferation, independently, because of distinct components in its structure.

Topics: Analysis of Variance; Animals; Benzimidazoles; Bromodeoxyuridine; Calixarenes; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclopentanes; Enzyme Activation; Focal Adhesion Kinase 1; Glioma; N-Acetylgalactosaminyltransferases; Rats; Tetrazolium Salts; Thiazoles; Time Factors; Wounds and Injuries