title: Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells.
abstract: Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Aldo Maria
authors.initials: AM
authors.lastname: Roccaro
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yasui
authors.forename: Norihiko
authors.initials: N
authors.lastname: Shiraishi
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.forename: Franco
authors.initials: F
authors.lastname: Dammacco
authors.forename: Paul Gerard
authors.initials: PG
authors.lastname: Richardson
authors.forename: Kenneth Carl
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D042683:Angiopoietin-1 / Q000096:biosynthesis / Q000235:genetics; D042702:Angiopoietin-2 / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D048708:Cell Growth Processes / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D007334:Insulin-Like Growth Factor I; D015850:Interleukin-6; D011719:Pyrazines; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors