| Title | Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma. | | Author(s) | Zhang J, Sattler M, Tonon G, Grabher C, Lababidi S, Zimmerhackl A, Raab MS, Vallet S, Zhou Y, Cartron MA, Hideshima T, Tai YT, Chauhan D, Anderson KC, Podar K | | Institution | Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Boston, MA 02115, USA. | | Source | Cancer Res 2009 Jun 15; 69(12):5082-90. | | MeSH | Adamantane
Angiogenesis Inhibitors
Animals
Blotting, Western
Cell Line, Tumor
Down-Regulation
Enzyme-Linked Immunosorbent Assay
Humans
Hydroquinones
Hypoxia-Inducible Factor 1, alpha Subunit
Immunohistochemistry
Mice
Mice, Nude
Multiple Myeloma
Neovascularization, Pathologic
Proto-Oncogene Proteins c-myc
Vascular Endothelial Growth Factor A
| | 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. | | Language | eng | | Pub Type(s) | Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
| | PubMed ID | 19509231 |
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