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Blood, 15 March 2008, Vol. 111, No. 6, pp. 3190-3199. Prepublished online as a Blood First Edition Paper on January 11, 2008; DOI 10.1182/blood-2007-10-115733. This Article Full Text (PDF) All Versions of this Article: blood-2007-10-115733v1 111/6/3190    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 Hussain, S.-R. A Articles by Grever, M. R Search for Related Content PubMed PubMed Citation Articles by Hussain, S.-R. A Articles by Grever, M. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 1, 2007 Accepted January 6, 2008 Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium Syed-Rehan A Hussain, David M Lucas*, Amy J Johnson, Thomas S Lin, Alan P Bakaletz, Vinh X Dang, Serge Viatchenko-Karpinski, Amy S Ruppert, John C Byrd, Periannan Kuppusamy, Elliott D Crouser, and Michael R Grever Department of Internal Medicine, Ohio State University, Columbus, OH, United States * Corresponding author; email: david.lucas{at}osumc.edu. Effective administration of flavopiridol in advanced-stage chronic lymphocytic leukemia (CLL) is often associated with early biochemical evidence of tumor cell lysis. Previous work using other cell types showed that flavopiridol impacts mitochondria, and in CLL cells flavopiridol down-regulates the mitochondrial protein Mcl-1. We therefore investigated mitochondrial structure and function in flavopiridol-treated CLL patient cells and in the lymphoblastic cell line 697 using concentrations and times at which tumor lysis is observed in treated patients. Mitochondrial membrane depolarization was detected in flavopiridol-treated CLL cells by six hours, well before the onset of cell death. Flavopiridol-induced mitochondrial depolarization was not blocked by caspase inhibitors or by the calcium chelator EGTA, but was reduced by Bcl-2 overexpression. Intracellular calcium mobilization was noted at early timepoints using fluorescence microscopy. Furthermore, electron paramagnetic resonance oximetry showed a gradual but significant reduction in cellular oxygen consumption rate by six hours, corresponding with ultrastructural mitochondrial damage detected by electron microscopy. These observations suggest that in CLL and 697 cells, flavopiridol mediates its cytotoxic effects via induction of the mitochondrial permeability transition and changes in intracellular calcium. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. M. Lucas, R. B. Edwards, G. Lozanski, D. A. West, J. D. Shin, M. A. Vargo, M. E. Davis, D. M. Rozewski, A. J. Johnson, B.-N. Su, et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo Blood, May 7, 2009; 113(19): 4656 - 4666. [Abstract] [Full Text] [PDF] F. T. Awan, N. E. Kay, M. E. Davis, W. Wu, S. M. Geyer, N. Leung, D. F. Jelinek, R. C. Tschumper, C. R. Secreto, T. S. Lin, et al. Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab Blood, January 15, 2009; 113(3): 535 - 537. [Abstract] [Full Text] [PDF]

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