Abstract
Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1α (Hif-1α) expression in MM cells, which is associated with oncogenic c-Myc. Adrug screen for anti-MM agents that decrease Hif-1α 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-1α-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-1α as a novel molecular target in MM and add another facet to anti-MM drug activity.
Original language | English |
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Pages (from-to) | 5082-5090 |
Number of pages | 9 |
Journal | Cancer Research |
Volume | 69 |
Issue number | 12 |
DOIs | |
Publication status | Published - 15 Jun 2009 |
Externally published | Yes |
Keywords
- Adamantane/analogs & derivatives
- 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
- Neovascularization, Pathologic/prevention & control
- Proto-Oncogene Proteins c-myc/metabolism
- Vascular Endothelial Growth Factor A/biosynthesis
ASJC Scopus subject areas
- Oncology
- Cancer Research