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.

Pharmacological Inhibition of Platelet-Tumor Cell Cross-Talk Prevents Platelet-Induced Overexpression of Cyclooxygenase-2 in HT29 Human Colon Carcinoma Cells

“…The results suggest that galectin-3 may act as a binding partner of platelet collagen receptors and, interestingly, imply that the binding is dependent on carbohydrate binding mediated by CRD and by homologous or heterologous protein-protein binding mediated by the collagen-like domain. Our results showing that Gal-3C prevented platelet-induced COX-2 overexpression in cancer cells also suggest that this could be a mechanism of its anticancer activity, as demonstrated in animal models (John et al, 2003;Mirandola et al, 2011). The contribution of PDGF, released by activated platelets, to the induction of COX-2 in HT29 cells was disclosed by blocking PDGFR activation with imatinib (Buchdunger et al, 2002) or by using a PDGF-neutralizing antibody.…”

The Two Endocytic Pathways Mediated by the Carbohydrate Recognition Domain and Regulated by the Collagen-like Domain of Galectin-3 in Vascular Endothelial Cells

“…This truncated version fails to support neutrophil adhesion [29] and fails to induce migration and capillary tubule formation in endothelial cells in vitro and angiogenesis in vivo [7]. Conversely, it inhibited tumor growth and metastasis in the orthotopic nude mouse model of human breast cancer and also inhibited tumor growth and increased the anticancer activity of Bortezomib in a murine model of human multiple myeloma [30]. Surprisingly, our data showed that G111-250, a CRD fragment similar to Gal3C, followed transport pathways different from those of the full-length protein.…”

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

“…21 Tumor growth was monitored by U266-specific IgE protein secretion in mouse serum. 22,23 While IL-2-expanded L-chainspecific CD8 C T cells can lyse the tumor cells very well in vitro, 17 these T cells only temporarily inhibited tumor cell growth in vivo (Fig. 1A).…”