Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors

PLoS One. 2013 May 7;8(5):e62818. doi: 10.1371/journal.pone.0062818. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / metabolism*
  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Aorta / physiology
  • Bone Marrow Cells / cytology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Endothelial Cells / drug effects
  • Humans
  • Mice
  • Multiple Myeloma / pathology*
  • Neovascularization, Physiologic / drug effects
  • Plicamycin / pharmacology*
  • Rats
  • Up-Regulation / drug effects*
  • Xenograft Model Antitumor Assays

Substances

  • Angiogenesis Inducing Agents
  • Angiogenesis Inhibitors
  • Plicamycin

Grants and funding

The study was in part supported by funds from the Belgian Foundation Against Cancer, the Fonds de la Recherche Scientifique Médicale, the Fonds National de la Recherche Scientifique (Belgium), the Fonds spéciaux de la Recherche (University of Liège), the DGO6 from the “Région Wallonne” (Belgium), and the Interuniversity Attraction Poles Program - Belgian Science Policy IUAP program 7/30 (Brussels, Belgium). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.