Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells

Aldo Maria Roccaro, Teru Hideshima, Noopur Raje, Shaji Kumar, Kenji Ishitsuka, Hiroshi Yasui, Norihiko Shiraishi, Domenico Ribatti, Beatrice Nico, Angelo Vacca, Franco Dammacco, Paul Gerard Richardson, Kenneth Carl Anderson

Research output: Contribution to journalArticlepeer-review

Abstract

Bone marrow angiogenesis plays an important role in the pathogenesis and progression in multiple myeloma. Recent studies have shown that proteasome inhibitor bortezomib (Velcade, formerly PS-341) can overcome conventional drug resistance in vitro and in vivo; however, its antiangiogenic activity in the bone marrow milieu has not yet been defined. In the present study, we examined the effects of bortezomib on the angiogenic phenotype of multiple myeloma patient-derived endothelial cells (MMEC). At clinically achievable concentrations, bortezomib inhibited the proliferation of MMECs and human umbilical vein endothelial cells in a dose-dependent and time-dependent manner. In functional assays of angiogenesis, including chemotaxis, adhesion to fibronectin, capillary formation on Matrigel, and chick embryo chorioallantoic membrane assay, bortezomib induced a dose-dependent inhibition of angiogenesis. Importantly, binding of MM.1S cells to MMECs triggered multiple myeloma cell proliferation, which was also abrogated by bortezomib in a dose-dependent fashion. Bortezomib triggered a dose-dependent inhibition of vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) secretion by the MMECs, and reverse transcriptase-PCR confirmed drug-related down-regulation of VEGF, IL-6, insulin-like growth factor-I, Angiopoietin 1 (Ang1), and Ang2 transcription. These data, therefore, delineate the mechanisms of the antiangiogenic effects of bortezomib on multiple myeloma cells in the bone marrow milieu.

Original languageEnglish
Pages (from-to)184-191
Number of pages8
JournalCancer Research
Volume66
Issue number1
DOIs
Publication statusPublished - Jan 1 2006

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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