SEARCH:   Advanced

Blood, 1 January 2006, Vol. 107, No. 1, pp. 222-231. Prepublished online as a Blood First Edition Paper on September 6, 2005; DOI 10.1182/blood-2005-05-1923. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 2005-05-1923v1 107/1/222    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 Carew, J. S. Articles by Huang, P. Search for Related Content PubMed PubMed Citation Articles by Carew, J. S. Articles by Huang, P. Related Collections Immunobiology Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL Jennifer S. Carew, Steffan T. Nawrocki, Yelena V. Krupnik, Kenneth Dunner, Jr, David J. McConkey, Michael J. Keating, and Peng Huang From the Departments of Molecular Pathology, Cancer Biology, and Leukemia, the University of Texas M. D. Anderson Cancer Center, Houston, TX. Previous studies showed that chronic lymphocytic leukemia (CLL) cells exhibit certain mitochondrial abnormalities including mtDNA mutations, increased superoxide generation, and aberrant mitochondrial biogenesis, which are associated with impaired apoptosis and reduced sensitivity to fludarabine. Here we report that CLL cells and multiple myeloma cells are highly sensitive to brefeldin A, an inhibitor of endoplasmic reticulum (ER) to Golgi protein transport currently being developed as a novel anticancer agent in a prodrug formulation. Of importance, brefeldin A effectively induced apoptosis in fludarabine-refractory CLL cells. Disruption of protein trafficking by brefeldin A caused the sequestration of the prosurvival factors APRIL and VEGF in the ER, leading to abnormal ER swelling and a decrease in VEGF secretion. Such ER stress and blockage of secretory protein traffic eventually resulted in Golgi collapse, activation of caspases, and cell death. Notably, the cellular sensitivity to this compound appeared to be independent of p53 status. Taken together, these findings suggest that malignant B cells may be highly dependent on ER-Golgi protein transport and that targeting this process may be a promising therapeutic strategy for B-cell malignancies, especially for those that respond poorly to conventional treatments. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. T. Nawrocki, J. S. Carew, K. H. Maclean, J. F. Courage, P. Huang, J. A. Houghton, J. L. Cleveland, F. J. Giles, and D. J. McConkey Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA Blood, October 1, 2008; 112(7): 2917 - 2926. [Abstract] [Full Text] [PDF] J. S. Carew, S. T. Nawrocki, V. K. Reddy, D. Bush, J. E. Rehg, A. Goodwin, J. A. Houghton, R. A. Casero Jr, L. J. Marton, and J. L. Cleveland The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib Cancer Res., June 15, 2008; 68(12): 4783 - 4790. [Abstract] [Full Text] [PDF] S. T. Nawrocki, J. S. Carew, L. Douglas, J. L. Cleveland, R. Humphreys, and J. A. Houghton Histone Deacetylase Inhibitors Enhance Lexatumumab-Induced Apoptosis via a p21Cip1-Dependent Decrease in Survivin Levels Cancer Res., July 15, 2007; 67(14): 6987 - 6994. [Abstract] [Full Text] [PDF] J. S. Carew, S. T. Nawrocki, C. N. Kahue, H. Zhang, C. Yang, L. Chung, J. A. Houghton, P. Huang, F. J. Giles, and J. L. Cleveland Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Abl-mediated drug resistance Blood, July 1, 2007; 110(1): 313 - 322. [Abstract] [Full Text] [PDF] L. A. Smit, D. Y.H. Hallaert, R. Spijker, B. de Goeij, A. Jaspers, A. P. Kater, M. H.J. van Oers, C. J.M. van Noesel, and E. Eldering Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity Blood, February 15, 2007; 109(4): 1660 - 1668. [Abstract] [Full Text] [PDF] K. W. Yip, X. Mao, P.Y. B. Au, D. W. Hedley, S. Chow, S. Dalili, J. D. Mocanu, C. Bastianutto, A. Schimmer, and F.-F. Liu Benzethonium Chloride: A Novel Anticancer Agent Identified by Using a Cell-Based Small-Molecule Screen. Clin. Cancer Res., September 15, 2006; 12(18): 5557 - 5569. [Abstract] [Full Text] [PDF]

	Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020