SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-07-2339. This Article Full Text (PDF) All Versions of this Article: 2002-07-2339v1 101/9/3674    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 Campas, C. Articles by Gil, J. Search for Related Content PubMed PubMed Citation Articles by Campas, C. Articles by Gil, J. Social Bookmarking                   What's this? Submitted August 1, 2002 Accepted December 23, 2002 Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes Clara Campas, Jose M Lopez, Antonio F Santidrian, Montserrat Barragan, Beatriz Bellosillo, Dolors Colomer, and Joan Gil* Unitat de Bioquimica, Departament de Ciencies Fisiologiques II, Universitat de Barcelona, Barcelona, Spain Unitat d'Hematopatologia, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain * Corresponding author; email: joangil{at}bellvitge.bvg.ub.es. Acadesine, 5-aminoimidazole-4-carboxamide (AICA) riboside, induced apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells in all samples tested (n=70). The IC50 for B-CLL cells was 380 ± 60 µM (n=5). The caspase inhibitor Z-VAD.fmk completely blocked acadesine-induced apoptosis, which involved the activation of caspases -3, -8 and -9 and cytochrome c release. Incubation of B-CLL cells with acadesine induced the phosphorylation of AMP-activated protein kinase (AMPK), indicating that it is activated by acadesine. Nitrobenzylthioinosine (NBTI), a nucleoside transport inhibitor, 5-iodotubercidin, an inhibitor of adenosine kinase, and adenosine completely inhibited acadesine-induced apoptosis and AMPK phosphorylation, demonstrating that incorporation of acadesine into the cell and its subsequent phosphorylation to AICA ribotide (ZMP) are necessary to induce apoptosis. Inhibitors of protein kinase A and MAP kinases did not protect from acadesine-induced apoptosis in B-CLL cells. Moreover, acadesine had no effect on p53 levels or phosphorylation, suggesting a p53-independent mechanism in apoptosis triggering. Normal B lymphocytes were as sensitive as B-CLL cells to acadesine-induced apoptosis. However, T cells from B-CLL patients were only slightly affected by acadesine at doses up to 4 mM. AMPK phosphorylation did not occur in T cells treated with acadesine. Intracellular levels of ZMP were higher in B-CLL cells than in T cells when both were treated with 0.5 mM acadesine, suggesting that ZMP accumulation is necessary to activate AMPK and induce apoptosis. These results suggest a new pathway involving AMPK in the control of apoptosis in B-CLL cells and raise the possibility of using acadesine in B-CLL treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. N. Bose, L. Maurmann, R. J. Mishur, L. Yasui, S. Gupta, W. S. Grayburn, H. Hofstetter, and T. Salley Non-DNA-binding platinum anticancer agents: Cytotoxic activities of platinum-phosphato complexes towards human ovarian cancer cells PNAS, November 25, 2008; 105(47): 18314 - 18319. [Abstract] [Full Text] [PDF] E. Schulz, J. Dopheide, S. Schuhmacher, S. R. Thomas, K. Chen, A. Daiber, P. Wenzel, T. Munzel, and J. F. Keaney Jr Suppression of the JNK Pathway by Induction of a Metabolic Stress Response Prevents Vascular Injury and Dysfunction Circulation, September 23, 2008; 118(13): 1347 - 1357. [Abstract] [Full Text] [PDF] A. Riboulet-Chavey, F. Diraison, L. K. Siew, F. S. Wong, and G. A. Rutter Inhibition of AMP-Activated Protein Kinase Protects Pancreatic {beta}-Cells From Cytokine-Mediated Apoptosis and CD8+ T-Cell-Induced Cytotoxicity Diabetes, February 1, 2008; 57(2): 415 - 423. [Abstract] [Full Text] [PDF] Y. Dagon, Y. Avraham, Y. Ilan, R. Mechoulam, and E. M. Berry Cannabinoids ameliorate cerebral dysfunction following liver failure via AMP-activated protein kinase FASEB J, August 1, 2007; 21(10): 2431 - 2441. [Abstract] [Full Text] [PDF] P. B. Bokko, L. Francione, E. Bandala-Sanchez, A. U. Ahmed, S. J. Annesley, X. Huang, T. Khurana, A. R. Kimmel, and P. R. Fisher Diverse Cytopathologies in Mitochondrial Disease Are Caused by AMP-activated Protein Kinase Signaling Mol. Biol. Cell, May 1, 2007; 18(5): 1874 - 1886. [Abstract] [Full Text] [PDF] M. C. Towler and D. G. Hardie AMP-Activated Protein Kinase in Metabolic Control and Insulin Signaling Circ. Res., February 16, 2007; 100(3): 328 - 341. [Abstract] [Full Text] [PDF] L. Coll-Mulet, D. Iglesias-Serret, A. F. Santidrian, A. M. Cosialls, M. de Frias, E. Castano, C. Campas, M. Barragan, A. F. de Sevilla, A. Domingo, et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells Blood, May 15, 2006; 107(10): 4109 - 4114. [Abstract] [Full Text] [PDF] Y. Andersson, H. Le, S. Juell, and O. Fodstad AMP-activated protein kinase protects against anti-epidermal growth factor receptor-Pseudomonas exotoxin A immunotoxin-induced MA11 breast cancer cell death. Mol. Cancer Ther., April 1, 2006; 5(4): 1050 - 1059. [Abstract] [Full Text] [PDF] Y. Dagon, Y. Avraham, I. Magen, A. Gertler, T. Ben-Hur, and E. M. Berry Nutritional Status, Cognition, and Survival: A NEW ROLE FOR LEPTIN AND AMP KINASE J. Biol. Chem., December 23, 2005; 280(51): 42142 - 42148. [Abstract] [Full Text] [PDF] A. F. Santidrian, C. Campas, L. Coll-Mulet, D. Iglesias-Serret, A. M. Cosialls, M. Defrias, A. Domindo, A. F. de Sevilla, G. Pons, and J. Gil Mechanism of Acadesine-Induced Apoptosis in B-Cell Neoplasms. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 4822 - 4822. [Abstract] M. Igata, H. Motoshima, K. Tsuruzoe, K. Kojima, T. Matsumura, T. Kondo, T. Taguchi, K. Nakamaru, M. Yano, D. Kukidome, et al. Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression Circ. Res., October 14, 2005; 97(8): 837 - 844. [Abstract] [Full Text] [PDF] N. Nath, S. Giri, R. Prasad, M. L. Salem, A. K. Singh, and I. Singh 5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis J. Immunol., July 1, 2005; 175(1): 566 - 574. [Abstract] [Full Text] [PDF] D. Nagata, R. Takeda, M. Sata, H. Satonaka, E. Suzuki, T. Nagano, and Y. Hirata AMP-Activated Protein Kinase Inhibits Angiotensin II-Stimulated Vascular Smooth Muscle Cell Proliferation Circulation, July 27, 2004; 110(4): 444 - 451. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020