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

Jing Zhang, Martin Sattler, Giovanni Tonon, Clemens Grabher, Samir Lababidi, Alexander Zimmerhackl, Marc S. Raab, Sonia Vallet, Yiming Zhou, Marie Astrid Cartron, Teru Hideshima, Yu Tzu Tai, Dharminder Chauhan, Kenneth C. Anderson, Klaus Podar*

*Korrespondierende:r Autor:in für diese Arbeit

Publikation: Beitrag in Fachzeitschrift (peer-reviewed)Artikel in Fachzeitschrift

85 Zitate (Scopus)

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.

OriginalspracheEnglisch
Seiten (von - bis)5082-5090
Seitenumfang9
FachzeitschriftCancer Research
Jahrgang69
Ausgabenummer12
DOIs
PublikationsstatusVeröffentlicht - 15 Juni 2009
Extern publiziertJa

ASJC Scopus Sachgebiete

  • Onkologie
  • Krebsforschung

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