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.
Highlights
Multiple myeloma (MM) is a malignancy characterized by clonal proliferation and accumulation of terminally differentiated plasma cells that produce immunoglobulin (Ig)
In an attempt to overcome these difficulties and to assess the potential of Gal-3C as a treatment for MM, the present study evaluated the efficacy of Gal-3C alone, and in combination with Bor in NOD/SCID immunodeficient mice implanted with human MM cells
Galectin-3 is expressed by MM cell lines Proteins derived from a panel of 9 human MM cell lines, namely MM-1S, MM-1RL, NCI-H929, RPMI-8226, 8226/Dox40, 8226/LR-5, ARP-1, ARK-B, and U266, were analyzed by Western blot to detect galectin-3 expression
Summary
Multiple myeloma (MM) is a malignancy characterized by clonal proliferation and accumulation of terminally differentiated plasma cells that produce immunoglobulin (Ig). The malignant plasma cells are found in the bone marrow and extramedullary locations. The American Cancer Society estimated that there were more than 20,000 new cases of MM in the US in 2010. Chemotherapy induces complete tumor regression in 50% of patients but the median survival of MM is only about 5 years [1]. The introduction of novel drugs such as thalidomide, lenalidomide, and bortezomib (Bor) that are thought to target specific intracellular pathways and affect cellular interactions with the tumor microenvironment, have aided in the treatment of MM especially in management of elderly patients [2]. Arguably the course of the disease has not fundamentally changed since the 1960s
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