Data from Lenalidomide Restrains Motility and Overangiogenic Potential of Bone Marrow Endothelial Cells in Patients with Active Multiple Myeloma

Abstract

<div>Abstract<p><b>Purpose:</b> To determine the <i>in vivo</i> and <i>in vitro</i> antiangiogenic power of lenalidomide, a “lead compound” of IMiD immunomodulatory drugs in bone marrow (BM) endothelial cells (EC) of patients with multiple myeloma (MM) in active phase (MMEC).</p><p><b>Experimental Design:</b> The antiangiogenic effect <i>in vivo</i> was studied using the chorioallantoic membrane (CAM) assay. Functional studies <i>in vitro</i> (angiogenesis, “wound” healing and chemotaxis, cell viability, adhesion, and apoptosis) were conducted in both primary MMECs and ECs of patients with monoclonal gammopathies (MGUS) of undetermined significance (MGEC) or healthy human umbilical vein endothelial cells (HUVEC). Real-time reverse transcriptase PCR, Western blotting, and differential proteomic analysis were used to correlate morphologic and biological EC features with the lenalidomide effects at the gene and protein levels.</p><p><b>Results:</b> Lenalidomide exerted a relevant antiangiogenic effect <i>in vivo</i> at 1.75 μmol/L, a dose reached in interstitial fluids of patients treated with 25 mg/d. <i>In vitro</i>, lenalidomide inhibited angiogenesis and migration of MMECs, but not of MGECs or control HUVECs, and had no effect on MMEC viability, apoptosis, or fibronectin- and vitronectin-mediated adhesion. Lenalidomide-treated MMECs showed changes in VEGF/VEGFR2 signaling pathway and several proteins controlling EC motility, cytoskeleton remodeling, and energy metabolism pathways.</p><p><b>Conclusions:</b> This study provides information on the molecular mechanisms associated with the antimigratory and antiangiogenic effects of lenalidomide in primary MMECs, thus giving new avenues for effective endothelium-targeted therapies in MM. <i>Clin Cancer Res; 17(7); 1935–46. ©2011 AACR</i>.</p></div>