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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2565-2570. Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-06-032664. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2006-06-032664v1 109/6/2565    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Veschini, L. Articles by Ferrero, E. Search for Related Content PubMed PubMed Citation Articles by Veschini, L. Articles by Ferrero, E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Hypoxia-inducible transcription factor–1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib Lorenzo Veschini1, Daniela Belloni1, Chiara Foglieni2, Maria Giulia Cangi3, Marina Ferrarini1, Federico Caligaris-Cappio1,4, and Elisabetta Ferrero1 1 Laboratory of Tumor Immunology and Department of Oncology, 2 Department of Cardiology, and 3 Department of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) H San Raffaele, Milan, Italy; 4 Vita-Salute San Raffaele University School of Medicine, Milan, Italy Angiogenesis is a complex, orchestrated process that plays a critical role in several conditions and has special relevance in the progression of cancer. Hypoxia is the major stimulus for angiogenesis, and hypoxia-inducible transcription factor–1 alpha (HIF-1) is its key mediator. We set up a novel in vitro model of HIF-1 up-regulation by treating human umbilical vein endothelial cells (HUVECs) with the hypoxia-mimicking deferoxamine (DFO) and found that this condition was sufficient to promote angiogenesis, like the well-known HUVEC model cultured under low pO2. The proteasome inhibitor bortezomib, which induces strong apoptosis in cancer cells, abrogated proliferation and angiogenesis of HUVECs when used at a high concentration (100 nM), yet promoted both functions at a low dosage (10 nM). This double-edged effect appeared to be mediated by differential effects exerted by the different concentrations of bortezomib on 2 master regulators of tumor-associated angiogenesis, HIF-1 and nuclear factor kappa B (NF-kB). Significantly, when HUVECs were induced to express HIF-1 prior to bortezomib treatment, proliferative and angiogenic responses were abolished, and a greatly enhanced proapoptotic effect was promoted with both concentrations of the drug. These findings indicate that HIF-1 up-regulation may sensitize endothelial cells to the antiangiogenic and proapoptotic effects of bortezomib and might be exploited to target tumor-associated vessels in the course of antiangiogenic therapies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Ruan, K. Hajjar, S. Rafii, and J. P. Leonard Angiogenesis and antiangiogenic therapy in non-Hodgkin's lymphoma Ann. Onc., March 1, 2009; 20(3): 413 - 424. [Abstract] [Full Text] [PDF] Z. Lin, M. Bazzaro, M.-C. Wang, K. C. Chan, S. Peng, and R. B.S. Roden Combination of Proteasome and HDAC Inhibitors for Uterine Cervical Cancer Treatment Clin. Cancer Res., January 15, 2009; 15(2): 570 - 577. [Abstract] [Full Text] [PDF] D. R. Fels, J. Ye, A. T. Segan, S. J. Kridel, M. Spiotto, M. Olson, A. C. Koong, and C. Koumenis Preferential Cytotoxicity of Bortezomib toward Hypoxic Tumor Cells via Overactivation of Endoplasmic Reticulum Stress Pathways Cancer Res., November 15, 2008; 68(22): 9323 - 9330. [Abstract] [Full Text] [PDF]

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