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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3982-3988. Prepublished online as a Blood First Edition Paper on December 21, 2006; DOI 10.1182/blood-2006-10-053959. This Article Full Text (PDF) All Versions of this Article: blood-2006-10-053959v1 109/9/3982    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 Kashkar, H. Articles by Kronke, M. Search for Related Content PubMed PubMed Citation Articles by Kashkar, H. Articles by Kronke, M. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 23, 2006 Accepted December 12, 2006 NF-kB independent down-regulation of XIAP by bortezomib sensitizes HL B-cells against cytotoxic drugs Hamid Kashkar*, Anke Deggerich, Jens-Michael Seeger, Benjamin Yazdanpanah, Katja Wiegmann, Dirk Haubert, Carola Pongratz, and Martin Kronke Institute for Medical Microbiology, Immunology and Hygiene, and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany * Corresponding author; email: h.kashkar{at}uni-koeln.de. The proteasome inhibitor, bortezomib, has been shown to possess promising anti-tumor activity and significant efficacy against a variety of malignancies. Different studies demonstrated that bortezomib breaks the chemoresistance in different tumor cells basically by altering nuclear factor-kB (NF-kB) activity. NF-kB has been shown to be constitutively active in the vast majority of primary Hodgkin-Reed-Sternberg (H-RS) cells in lymph node sections and in Hodgkin's lymphoma (HL) cell lines and was suggested to be a central molecular switch in apoptosis resistance in HL. Here we report a bimodal effect of bortezomib in HL cells. Whereas high-dose bortezomib induced direct cytotoxicity which correlated with decreased NF-kB activity, low-dose bortezomib sensitized HL cells against a variety of cytotoxic drugs without altering NF-kB action. Strikingly, bortezomib induced marked XIAP down-regulation at the post-translational level which was independent of the NF-kB status. Similarly, RNA interference (RNAi)-mediated XIAP down-regulation generated susceptibility to cytostatic agents. The results identify XIAP as an NF-kB independent target of bortezomib action that controls the chemoresistant phenotype of HL cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: X. Zhang, T. Zou, J. N. Rao, L. Liu, L. Xiao, P.-Y. Wang, Y.-H. Cui, M. Gorospe, and J.-Y. Wang Stabilization of XIAP mRNA through the RNA binding protein HuR regulated by cellular polyamines Nucleic Acids Res., October 13, 2009; (2009) gkp755v1. [Abstract] [Full Text] [PDF] K.-F. Chen, P.-Y. Yeh, C. Hsu, C.-H. Hsu, Y.-S. Lu, H.-P. Hsieh, P.-J. Chen, and A.-L. Cheng Bortezomib Overcomes Tumor Necrosis Factor-related Apoptosis-inducing Ligand Resistance in Hepatocellular Carcinoma Cells in Part through the Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway J. Biol. Chem., April 24, 2009; 284(17): 11121 - 11133. [Abstract] [Full Text] [PDF] M. IIJIMA, I. MOMOSE, and D. IKEDA TP-110, a New Proteasome Inhibitor, Down-regulates IAPs in Human Multiple Myeloma Cells Anticancer Res, April 1, 2009; 29(4): 977 - 985. [Abstract] [Full Text] [PDF] K.-F. Chen, P.-Y. Yeh, K.-H. Yeh, Y.-S. Lu, S.-Y. Huang, and A.-L. Cheng Down-regulation of Phospho-Akt Is a Major Molecular Determinant of Bortezomib-Induced Apoptosis in Hepatocellular Carcinoma Cells Cancer Res., August 15, 2008; 68(16): 6698 - 6707. [Abstract] [Full Text] [PDF]

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