title: Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma.
abstract: Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1alpha (Hif-1alpha) expression in MM cells, which is associated with oncogenic c-Myc. A drug screen for anti-MM agents that decrease Hif-1alpha and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1alpha-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1alpha as a novel molecular target in MM and add another facet to anti-MM drug activity.
authors.affiliation: Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Boston, MA 02115, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.forename: Clemens
authors.initials: C
authors.lastname: Grabher
authors.forename: Samir
authors.initials: S
authors.lastname: Lababidi
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimmerhackl
authors.forename: Marc S
authors.initials: MS
authors.lastname: Raab
authors.forename: Sonia
authors.initials: S
authors.lastname: Vallet
authors.forename: Yiming
authors.initials: Y
authors.lastname: Zhou
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Cartron
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D006873:Hydroquinones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C404397:NSC 680410; D016271:Proto-Oncogene Proteins c-myc; D042461:Vascular Endothelial Growth Factor A; D000218:Adamantane