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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 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 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 CrossRef Google Scholar Articles by Oerlemans, R. Articles by Jansen, G. PubMed PubMed Citation Articles by Oerlemans, R. Articles by Jansen, G. Related Collections Neoplasia Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein Ruud Oerlemans1,*, Niels E. Franke2,*, Yehuda G. Assaraf3, Jacqueline Cloos2, Ina van Zantwijk2, Celia R. Berkers4, George L. Scheffer5, Kabir Debipersad1, Katharina Vojtekova2, Clara Lemos6, Joost W. van der Heijden1, Bauke Ylstra7, Godefridus J. Peters6, Gertjan L. Kaspers2, Ben A. C. Dijkmans1, Rik J. Scheper5, and Gerrit Jansen1 Departments of1 Rheumatology and 2 Pediatric Oncology/Hematology, VUMC Institute for Cancer & Immunology, VU University Medical Center, Amsterdam, The Netherlands; 3 The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel; 4 Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands; and Departments of5 Pathology and 6 Medical Oncology, and 7 Microarray Facility, VUMC Institute for Cancer & Immunology, VU University Medical Center, Amsterdam, The Netherlands The proteasome inhibitor bortezomib 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. Toward this end, we here developed high levels (45- to 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 (1) an Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome β5-subunit (PSMB5) protein, (2) a dramatic overexpression (up to 60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7, (3) high levels of cross-resistance to β5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugs, (4) no marked changes in chymotrypsin-like proteasome activity, and (5) restoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing of PSMB5 gene expression. Collectively, these findings establish a novel mechanism 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]

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