Synthetic Inhibitors of Galectin-1 and -3 Selectively Modulate Homotypic Cell Aggregation and Tumor Cell Apoptosis

Anticancer Research January 2009 vol. 29no. 1 403-410

IDA IURISCI1, ALBANA CUMASHI1, ANDREI A. SHERMAN2,YURY E. TSVETKOV2, NICOLA TINARI1, ENZA PICCOLO1,MAURIZIA D'EGIDIO1, VINCENZO ADAMO4, CLARA NATOLI1, GABRIEL A. RABINOVICH3, STEFANO IACOBELLI1, NIKOLAY E. NIFANTIEV

　　1 Department of Oncology and Neurosciences, Foundation University, Italy

　  2 Laboratory of Glycoconjugate Chemistry, N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation

　　3 Laboratory of Immunopathology, Institute of Biology and Experimental Medicine, Argentina

　　4 Section of Medical Oncology, University of Messina, Italy

Abstract

　 　Background: Galectins have emerged as critical regulators of tumor progression and metastasis, by modulating different biological events including homotypic cell aggregation, apoptosis, migration, angiogenesis and immune escape. Therefore, galectin inhibitors might represent novel therapeutic agents for cancer. Materials and Methods: A series of structural analogs of the disaccharide methyl β-lactosaminide were screened as potential galectin inhibitors by examining their capability to block binding of galectin-1 and/or galectin-3 to LGalS3BP in solid-phase assays. To demonstrate any functional role in vitro, oligosaccharides were characterized by their ability to regulate tumor cell apoptosis and LGalS3BP-induced homotypic cell aggregation. Results: Oligosaccharides differentially inhibited binding of each galectin to LGalS3BP. Compounds containing longer oligosaccharide chains were found to be potent inhibitors of both galectins under static conditions. Strikingly, the most active compound in inhibiting homotypic cell aggregation and tumor cell apoptosis was found to be allyl lactoside, which paradoxically exhibited a modest inhibitory capacity for blocking galectin-1 and -3 binding to LGalS3BP. Conclusion: Allyl lactoside represents a novel powerful inhibitor of tumor-associated homotypic cell aggregation and apoptosis. Further investigations are required to remodel selective and potent inhibitors capable of specifically modulating the activity of different members of the galectin family.