neurostatin and Brain-Neoplasms

In spite of their low incidence, central nervous system tumors have elevated morbidity and mortality, being responsible for 2.3% of total cancer deaths. The ganglioside O-acetylated GD1b (O-Ac GD1b; neurostatin), present in the mammalian brain, and the semi-synthetic O-butyrylated GD1b (O-But GD1b) are potent glioma proliferation inhibitors, appearing as possible candidates for the treatment of nervous system tumors. Tumoral cell division inhibitory activity in culture correlated with growth inhibition of glioma xenotransplants in Foxn1(nu) nude mice and intracranial glioma allotransplants. Both O-Ac GD1b and O-But GD1b inhibited in vivo cell proliferation, induced cell cycle arrest, and potentiated immune cell response to the tumor. Furthermore, the increased stability of the butyrylated compound (O-But GD1b) enhanced its activity with respect to the acetylated ganglioside (neurostatin). These results are the first report of the antitumoral activity of neurostatin and a neurostatin-like compound in vivo and indicate that semi-synthetic O-acetylated and O-butyrylated gangliosides are potent antitumoral compounds that should be considered in strategies for brain tumor treatment.

Topics: Acetylation; Animals; Antineoplastic Agents; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Separation; Flow Cytometry; Gangliosides; Glioma; Glycosphingolipids; Immunohistochemistry; Male; Mice; Mice, Nude; Rats; Rats, Sprague-Dawley; Xenograft Model Antitumor Assays

Neurostatin, a mammalian brain inhibitor of division of astroblast and astrocytoma cells, was characterized as the disialoganglioside GD1b, 9-O-acetylated on the outer sialic acid residue (Galbeta1-->3GalNAcbeta1-->4(9-O-Ac-NeuAcalpha2-->8NeuAcalpha2-->3)Galbeta1-->4Glcbeta1-->1'-ceramide). Using semisynthetic approaches, we prepared and tested different gangliosides O-acetylated in the sialic acid and compared them to non-O-acetylated partners as inhibitors of U-373 glioma cells. Athough the O-acetylation of the sialic acid was the most important molecular feature for the antiproliferative activity of O-acetylated gangliosides, monosaccharide links Galbeta1--> 3GalNAcbeta1 and NeuAcalpha2-->8NeuAcalpha2 enhanced the inhibitory activity.

Topics: Acetylation; Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Cell Division; Cell Line, Tumor; Gangliosides; Glycolipids; Glycosphingolipids; Humans; N-Acetylneuraminic Acid; Structure-Activity Relationship