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Prepublished online as a Blood First Edition Paper on July 31, 2003August 7, 2003; DOI 10.1182/blood-2003-03-0737. This Article Full Text (PDF) All Versions of this Article: 2003-03-0737v1 2003-03-0737v2 102/10/3765    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 Yu, C. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Yu, C. Articles by Grant, S. Social Bookmarking                   What's this? Submitted March 12, 2003 Accepted July 9, 2003 The proteasome inhibitor bortezomib interacts synergistically with histone deacetylase inhibitors to induce apoptosis in Bcr/Abl+ cells sensitive and resistant to STI571 Chunrong Yu, Mohamed Rahmani, Daniel Conrad, Mark Subler, Paul Dent, and Steven Grant* Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Department of Biochemistry, Virginia Commonwealth University, Richmond, VA, USA; Department of Pharmacology, Virginia Commonwealth University, Richmond, VA, USA Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, USA Department of Microbiology, Virginia Commonwealth University, Richmond, VA, USA Department of Human Genetics, Virginia Commonwealth University, Richmond, VA, USA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between the proteasome inhibitor bortezomib (VelcadeTM (previously known as PS-341) and histone deacetylease inhibitors (HDIs) have been examined in Bcr/Abl+ human leukemia cells (K562 and LAMA 84). Co-exposure of cells (24-48hr) to minimally toxic concentrations of bortezimib + either SAHA or sodium butyrate (SB) resulted in a striking increase in mitochondrial injury, caspase activation, and apoptosis, reflected by caspase-3 and -8 cleavage and PARP degradation. These events were accompanied by down-regulation of the Raf-1/MEK/ERK pathway as well as diminished expression of Bcr/Abl and cyclin D1, cleavage of p21CIP1 and pRb, and induction of the stress-related kinases JNK and p38 MAPK. Transient transfection of cells with a constitutively active MEK construct significantly protected them from bortezimib /SAHA-mediated lethality. Co-administration of bortezimib and SAHA resulted in increased ROS generation and diminished NF-B activation; moreover, the free radical scavenger L-N-acetylcyteine (LNAC) blocked bortezimib /SAHA-related ROS generation, induction of JNK and p21CIP1, and apoptosis. Lastly, this regimen potently induced apoptosis in STI571 (imatinib mesylate)-resistant K562 cells and CD34+ mononuclear cells obtained from a patient with STI571-resistant disease, as well as in Bcr/Abl- leukemia cells (e.g., HL-60, U937, Jurkat). Together, these findings raise the possibility that combined proteasome/histone deacetylase inhibition may represent a novel strategy in leukemia, including apoptosis-resistant Bcr/Abl+ hematologic malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Hideshima, H. Ikeda, D. Chauhan, Y. Okawa, N. Raje, K. Podar, C. Mitsiades, N. C. Munshi, P. G. Richardson, R. D. Carrasco, et al. 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