ZFIN ID: ZDB-PUB-090617-2
Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma
Zhang, J., Sattler, M., Tonon, G., Grabher, C., Lababidi, S., Zimmerhackl, A., Raab, M.S., Vallet, S., Zhou, Y., Cartron, M.A., Hideshima, T., Tai, Y.T., Chauhan, D., Anderson, K.C., and Podar, K.
Date: 2009
Source: Cancer research   69(12): 5082-5090 (Journal)
Registered Authors: Grabher, Clemens
Keywords: c-Myc, Hif-1α, multiple myeloma, angiogenesis, bortezomib, enzastaurin, lenalidomide, adaphostin
MeSH Terms:
  • Adamantane/analogs & derivatives
  • Adamantane/pharmacology
  • Angiogenesis Inhibitors/pharmacology
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Down-Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hydroquinones/pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit/metabolism*
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Multiple Myeloma/blood supply*
  • Multiple Myeloma/metabolism
  • Neovascularization, Pathologic/prevention & control*
  • Proto-Oncogene Proteins c-myc/metabolism*
  • Vascular Endothelial Growth Factor A/biosynthesis
PubMed: 19509231 Full text @ Cancer Res.
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.