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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1971-1980. Prepublished online as a Blood First Edition Paper on June 19, 2008; DOI 10.1182/blood-2007-12-126946. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2007-12-126946v1 112/5/1971    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 Balakrishnan, K. Articles by Gandhi, V. Search for Related Content PubMed PubMed Citation Articles by Balakrishnan, K. Articles by Gandhi, V. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 3, 2007 Accepted April 13, 2008 Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells Kumudha Balakrishnan, William G Wierda, Michael J Keating, and Varsha Gandhi* Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX Leukemia Department, M.D. Anderson Cancer Center, Houston, TX * Corresponding author; email: vgandhi{at}mdanderson.org. Gossypol, a cottonseed extract derivative, acts as a BH3-mimetic, binding to the BH3 pocket of anti-apoptotic proteins and displacing pro-death partners to induce apoptosis. However, knowledge on the molecular underpinnings of its downstream effects is limited. Since chronic lymphocytic leukemia (CLL) cells express high levels of anti-apoptotic proteins that act as a survival mechanism for these replicationally quiescent lymphocytes, we investigated whether gossypol induces apoptosis in these cells and what mechanism underlies gossypol-mediated cytotoxicity. Gossypol induced cell death in a concentration- and time-dependent manner; 24-hour incubation with 30 µM gossypol resulted in 50% cell death (median; range, 10-80%; n = 47) that was not abrogated by pan-specific caspase inhibitor. Starting at 4 hours, the mitochondrial outer membrane was significantly permeabilized (median, 77%; range, 54-93%; n = 15). Mitochondrial outer membrane permeablistaion (MOMP) was concurrent with increased production of reactive oxygen species (ROS); however, antioxidants did not abrogate gossypol-induced cell death. Mitochondrial membrane permeabilization was also associated with loss of intracellular ATP, activation of BAX, and release of cytochrome c and apoptosis-inducing factor (AIF), which was translocated to the nucleus. Blocking AIF translocation resulted in a decreased apoptosis, suggesting that AIF contributes to gossypol-mediated cytotoxicity in CLL lymphocytes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Chen, W. G. Wierda, S. Chubb, R. E. Hawtin, J. A. Fox, M. J. Keating, V. Gandhi, and W. Plunkett Mechanism of action of SNS-032, a novel cyclin-dependent kinase inhibitor, in chronic lymphocytic leukemia Blood, May 7, 2009; 113(19): 4637 - 4645. [Abstract] [Full Text] [PDF] T. J. Kipps Chronic Lymphocytic Leukemia: Advances in Assessing Prognosis and Therapy ASCO Educational Book, January 1, 2009; 2009(1): 385 - 393. [Abstract] [Full Text] [PDF] K. Balakrishnan, J. A. Burger, W. G. Wierda, and V. Gandhi AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance Blood, January 1, 2009; 113(1): 149 - 153. [Abstract] [Full Text] [PDF] V. Gandhi, K. Balakrishnan, and L. S. Chen Mcl-1: the 1 in CLL Blood, November 1, 2008; 112(9): 3538 - 3540. [Full Text] [PDF]

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