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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2489-2499. Prepublished online as a Blood First Edition Paper on June 18, 2008; DOI 10.1182/blood-2007-08-104950. This Article Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2007-08-104950v1 112/6/2489    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 Oerlemans, R. Articles by Jansen, G. Search for Related Content PubMed PubMed Citation Articles by Oerlemans, R. Articles by Jansen, G. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 1, 2007 Accepted May 11, 2008 Molecular basis of bortezomib/Velcade® resistance: proteasome subunit 5 (PSMB5) gene mutation and overexpression of PSMB5 protein Ruud Oerlemans, Niels E Franke, Yehuda G Assaraf, Jacqueline Cloos, Ina van Zantwijk, Celia R. Berkers, George L Scheffer, Kabir Debipersad, Katharina Vojtekova, Clara Lemos, Joost W van der Heijden, Bauke Ylstra, Godefridus J Peters, Gertjan L. Kaspers, Ben AC Dijkmans, Rik J Scheper, and Gerrit Jansen* Department of Rheumatology, VU University Medical Ctr, Amsterdam, Netherlands Department of Pediatric Oncology/Hematology, VU University Medical Ctr, Amsterdam, Netherlands The Fred Wyszkowski Cancer Research Laboratory, The Technion-Israel Institute of Technology, Haifa, Israel Division of Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands Department of Pathology, VU University Medical Ctr, Amsterdam, Netherlands Department of Medical Oncology, VU University Medical Ctr, Amsterdam, Netherlands Microarray Facility, VU University Medical Ctr, Amsterdam, Netherlands * Corresponding author; email: g.jansen{at}vumc.nl. The proteasome inhibitor bortezomib (Velcade®) is a novel anticancer drug that has shown promise in the treatment of refractory multiple myeloma. However, its clinical efficacy has been hampered by the emergence of drug resistance phenomena, the molecular basis of which remains elusive. Towards this end, we here developed high levels (45-129 fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib. Study of the molecular mechanism of bortezomib-resistance in these cells revealed: (a) An Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome 5 subunit (PSMB5) protein, (b) A dramatic overexpression (up to 60-fold) of PSMB5 protein but of other proteasome subunits including PSMB6, PSMB7 and PSMA7, (c) High levels of cross-resistance to 5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262 and ALLN, but not to a broad spectrum of chemotherapeutic drugs (d) No marked changes in chymotrypsine-like proteasome activity, and (e) Restoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing of PSMB5 gene expression. Collectively, these findings establish a novel mechanisms of bortezomib-resistance associated with the selective overexpression of a mutant PSMB5 protein. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Many facets of bortezomib resistance/susceptibility Shaji Kumar and S. Vincent Rajkumar Blood 2008 112: 2177-2178. [Full Text] [PDF] This article has been cited by other articles: O. A. O'Connor, A. K. Stewart, M. Vallone, C. J. Molineaux, L. A. Kunkel, J. F. Gerecitano, and R. Z. Orlowski A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies Clin. Cancer Res., November 15, 2009; 15(22): 7085 - 7091. [Abstract] [Full Text] [PDF] J. Kern, G. Untergasser, C. Zenzmaier, B. Sarg, G. Gastl, E. Gunsilius, and M. Steurer GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib Blood, October 29, 2009; 114(18): 3960 - 3967. [Abstract] [Full Text] [PDF] F. Parlati, S. J. Lee, M. Aujay, E. Suzuki, K. Levitsky, J. B. Lorens, D. R. Micklem, P. Ruurs, C. Sylvain, Y. Lu, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome Blood, October 15, 2009; 114(16): 3439 - 3447. [Abstract] [Full Text] [PDF] G. Bianchi, L. Oliva, P. Cascio, N. Pengo, F. Fontana, F. Cerruti, A. Orsi, E. Pasqualetto, A. Mezghrani, V. Calbi, et al. The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition Blood, March 26, 2009; 113(13): 3040 - 3049. [Abstract] [Full Text] [PDF] D. M. Schewe and J. A. Aguirre-Ghiso Inhibition of eIF2{alpha} Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy Cancer Res., February 15, 2009; 69(4): 1545 - 1552. [Abstract] [Full Text] [PDF]

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