title: Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors.
abstract: Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we evaluated its anti-myeloma effects in the syngenic 5TGM1 model in vitro as well as in vivo. In vitro, MTM inhibited DNA synthesis of 5TGM1 cells with an IC50 of 400 nM and induced an arrest in cell cycle progression at the G1/S transition point. Western-blot revealed an up-regulation of p53, p21 and p27 and an inhibition of c-Myc, while SP1 remained unaffected. In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment. The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation. These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation.
authors.affiliation: Laboratory of Hematology, Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), University of Liège, Liège, Belgium.
authors.forename: Eléonore
authors.initials: E
authors.lastname: Otjacques
authors.forename: Marilène
authors.initials: M
authors.lastname: Binsfeld
authors.forename: Natacha
authors.initials: N
authors.lastname: Rocks
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.forename: Yves
authors.initials: Y
authors.lastname: Beguin
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.forename: Jo
authors.initials: J
authors.lastname: Caers
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D008926:Plicamycin / Q000494:pharmacology*; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D008926:Plicamycin