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Cancer Res. 2009 Jun 15;69(12):5082-90. doi: 10.1158/0008-5472.CAN-08-4603. Epub 2009 Jun 9.

Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1alpha-dependent pathway in multiple myeloma.

Author information

1
Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics, Boston, MA 02115, USA.

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.

PMID:
19509231
DOI:
10.1158/0008-5472.CAN-08-4603
[Indexed for MEDLINE]
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