title: Antitumor agent calixarene 0118 targets human galectin-1 as an allosteric inhibitor of carbohydrate binding.
abstract: Calix[4]arene compound 0118 is an angiostatic agent that inhibits tumor growth in mice. Although 0118 is a topomimetic of galectin-1-targeting angiostatic amphipathic peptide Anginex, we had yet to prove that 0118 targets galectin-1. Galectin-1 is involved in pathological disorders like tumor endothelial cell adhesion and migration and therefore presents a relevant target for therapeutic intervention against cancer. Here, (15)N-(1)H HSQC NMR spectroscopy demonstrates that 0118 indeed targets galectin-1 at a site away from the lectin's carbohydrate binding site and thereby attenuates lactose binding to the lectin. Flow cytometry and agglutination assays show that 0118 attenuates binding of galectin-1 to cell surface glycans, and the inhibition of cell proliferation by 0118 is found to be correlated with the cellular expression of the lectin. In general, our data indicate that 0118 targets galectin-1 as an allosteric inhibitor of glycan/carbohydrate binding. This work contributes to the clinical development of antitumor calixarene compound 0118.
authors.affiliation: Department of Biochemistry, Molecular Biology & Biophysics, University of Minnesota Health Sciences Center, 6-155 Jackson Hall, 321 Church Street, Minneapolis, Minnesota 55455, United States.
authors.forename: Ruud P M
authors.initials: RP
authors.lastname: Dings
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Miller
authors.forename: Irina
authors.initials: I
authors.lastname: Nesmelova
authors.forename: Lucile
authors.initials: L
authors.lastname: Astorgues-Xerri
authors.forename: Nigam
authors.initials: N
authors.lastname: Kumar
authors.forename: Maria
authors.initials: M
authors.lastname: Serova
authors.forename: Xuimei
authors.initials: X
authors.lastname: Chen
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hoye
authors.forename: Kevin H
authors.initials: KH
authors.lastname: Mayo
mesh_terms: D000372:Agglutination Tests; D000494:Allosteric Regulation; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D047250:Calixarenes / Q000494:pharmacology*; D050260:Carbohydrate Metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D037483:Galectin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D011485:Protein Binding
chemical_list: D000970:Antineoplastic Agents; D037483:Galectin 1; C445499:LGALS1 protein, human; C530377:compound 0118; D047250:Calixarenes