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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 29, 2006 Accepted November 1, 2006 Hypoxia-inducible transcription factor-1alpha determines sensitivity of endothelial cells to the proteosome inhibitor Bortezomib Lorenzo Veschini, Daniela Belloni, Chiara Foglieni, M. Giulia Cangi, Marina Ferrarini, Federico Caligaris-Cappio, and Elisabetta Ferrero* IRCCS H San Raffaele, Italy Vita-Salute San Raffaele University School of Medicine, Italy * Corresponding author; email: ferrero.elisabetta{at}hsr.it. 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 HIF-1 is its key mediator. We set up a novel in vitro model of HIF-1 upregulation by treating HUVEC 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 HUVEC when used at high concentration (100 nM) yet promoted both functions at low dosage (10 nM). This double-edged effect appeared to be mediated by differential effects exerted by the different concentrations of Bortezomib on two master regulators of tumor-associated angiogenesis, HIF-1 and NF-kB. Significantly, when HUVEC 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 upregulation 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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