title: Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma.
abstract: Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM.
authors.affiliation: Division of Hematology & Oncology, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, Texas, United States of America.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Mirandola
authors.forename: Yuefei
authors.initials: Y
authors.lastname: Yu
authors.forename: Kitty
authors.initials: K
authors.lastname: Chui
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Jenkins
authors.forename: Everardo
authors.initials: E
authors.lastname: Cobos
authors.forename: Constance M
authors.initials: CM
authors.lastname: John
authors.forename: Maurizio
authors.initials: M
authors.lastname: Chiriva-Internati
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D000229:Dependovirus / Q000235:genetics; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007146:Immunoglobulin lambda-Chains / Q000276:immunology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D009101:Multiple Myeloma / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D037502:Galectin 3; D007146:Immunoglobulin lambda-Chains; D039302:Integrin alphaVbeta3; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins; D007073:Immunoglobulin E; D000069286:Bortezomib