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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4455-4462. Prepublished online as a Blood First Edition Paper on February 17, 2005; DOI 10.1182/blood-2004-05-1699. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-05-1699v1 105/11/4455    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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. Related Collections Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Cell death of bioenergetically compromised and transcriptionally challenged CLL lymphocytes by chlorinated ATP Kumudha Balakrishnan, Christine M. Stellrecht, Davide Genini, Mary Ayres, William G. Wierda, Michael J. Keating, Lorenzo M. Leoni, and Varsha Gandhi From the Departments of Experimental Therapeutics and Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California at San Diego, La Jolla, CA. Myeloid cell leukemia-1 (MCL-1) acts as a key survival factor for chronic lymphocytic leukemia (CLL) cells. In addition, dissipation of cellular bioenergy may impose a lethal effect on these quiescent cells. Previously, in multiple myeloma cell lines we demonstrated that halogenated adenosine (8-Cl-Ado) was phosphorylated to triphosphate (8-Cl–adenosine triphosphate [ATP]), which preferentially incorporated into mRNA and inhibited RNA synthesis by premature transcription termination. Furthermore, 8-Cl-ATP accumulation was associated with a decline in cellular bioenergy. Based on these actions, we hypothesized that 8-Cl-Ado would be ideal to target CLL lymphocytes. In the present study we demonstrate that leukemic lymphocytes incubated with 8-Cl-Ado display time- and dose-dependent increase in the accumulation of 8-Cl-ATP, with a parallel depletion of the endogenous ATP pool. Inhibition of global RNA synthesis resulted in a significant decline in the expression of transcripts with a short half-life such as MCL1. Consistent to this, protein expression of MCL-1 but not B-cell lymphoma–2 (BCL-2) was decreased. Furthermore, 8-Cl-ATP induced programmed cell death, as suggested by caspases activation, cleavage of caspase 3, and PARP (poly–adenosine diphosphate [ADP]–ribose polymerase), and increased DNA fragmentation. In conclusion, 8-Cl-Ado induces apoptosis in CLL lymphocytes by targeting cellular bioenergy as well as RNA transcription and translation of key survival genes such as MCL1. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. Balakrishnan, W. G. Wierda, M. J. Keating, and V. Gandhi Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells Blood, September 1, 2008; 112(5): 1971 - 1980. [Abstract] [Full Text] [PDF] C. M. Stellrecht, C. J. Phillip, F. Cervantes-Gomez, and V. Gandhi Multiple Myeloma Cell Killing by Depletion of the MET Receptor Tyrosine Kinase Cancer Res., October 15, 2007; 67(20): 9913 - 9920. [Abstract] [Full Text] [PDF] G. I. Shapiro Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment J. Clin. Oncol., April 10, 2006; 24(11): 1770 - 1783. [Abstract] [Full Text] [PDF] R. Chen, M. J. Keating, V. Gandhi, and W. Plunkett Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death Blood, October 1, 2005; 106(7): 2513 - 2519. [Abstract] [Full Text] [PDF] K. Balakrishnan, W. G. Wierda, M. J. Keating, and V. Gandhi Mechanisms of Cell Death of Chronic Lymphocytic Leukemia Lymphocytes by RNA-Directed Agent, 8-NH2-Adenosine Clin. Cancer Res., September 15, 2005; 11(18): 6745 - 6752. [Abstract] [Full Text] [PDF]

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