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Blood, 15 July 2004, Vol. 104, No. 2, pp. 509-518. Prepublished online as a Blood First Edition Paper on March 23, 2004; DOI 10.1182/blood-2003-12-4121. This Article Full Text (PDF) All Versions of this Article: 2003-12-4121v1 104/2/509    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 Dai, Y. Articles by Grant, S. Search for Related Content PubMed PubMed Citation Articles by Dai, Y. Articles by Grant, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 3, 2003 Accepted March 7, 2004 Bortezomib and Flavopiridol interact synergistically to induce apoptosis in chronic myeloid leukemia cells resistant to imatinib mesylate through both Bcr/Abl-dependent and -independent mechanisms Yun Dai, Mohamed Rahmani, Xin-Yan Pei, Paul Dent, and Steven Grant* Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA, USA Department of Radiation Oncology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA, USA Department of Medicine, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA, USA; Department of Biochemistry, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA, USA; Department of Pharmacology, Virginia Commonwealth University, Medical College of Virginia, Richmond, VA, USA * Corresponding author; email: stgrant{at}hsc.vcu.edu. Interactions between the CDK (cyclin-dependent kinase) inhibitor Flavopiridol and the proteasome inhibitor Bortezomib were examined in Bcr/Abl+ human leukemia cells. Co-exposure of K562 or LAMA84 cells to subtoxic concentration of Flavopiridol (150-200nM) and Bortezomib (5-8nM) resulted in a synergistic increase in mitochondrial dysfunction and apoptosis. These events were associated with a marked diminution in NF-B/DNA binding activity, enhanced phosphorylation of SEK1/MKK4, JNK, and p38 MAPK, down-regulation of Bcr/Abl, and a marked reduction in STAT3 and STAT5 activity. In imatinib-resistant K562 cells displaying increased Bcr/Abl expression, Bortezomib/Flavopiridol treatment markedly increased apoptosis in association with down-regulation of Bcr/Abl and Bcl-xL, and diminished phosphorylation of Lyn, Hck, CrkL, and Akt. Parallel studies were performed in imatinib-resistant LAMA84 cells exhibiting reduced expression of Bcr/Abl, but a marked increase in expression/activation of Lyn and Hck. Flavopiridol/Bortezomib effectively induced apoptosis in these cells in association with Lyn and Hck inactivation. The capacity of Flavopiridol to promote Bortezomib-mediated Bcr/Abl downregulation and apoptosis was mimicked by the P-TEFb inhibitor DRB. Finally, the Bortezomib/Flavopiridol regimen also potently induced apoptosis in Bcr/Abl- human leukemia cells. Collectively, these findings suggest that a strategy combining Flavopiridol and Bortezomib warrants further examination in chronic myelogenous leukemia and related hematologic malignancies. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. GUAN, L. ZHU, G. SOMLO, A. HUGHES, B. ZHOU, and Y. 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