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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-01-0075. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-01-0075v1 101/1/265    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 Sarfati, M. Articles by Merle-Béral, H. Search for Related Content PubMed PubMed Citation Articles by Sarfati, M. Articles by Merle-Béral, H. Related Collections Neoplasia Apoptosis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2003, Vol. 101, No. 1, pp. 265-269 NEOPLASIA Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells Marika Sarfati, Véronique Mateo, Sylvie Baudet, Manuel Rubio, Christine Fernandez, Fréderic Davi, Jacques-Louis Binet, Jozo Delic, and Hélène Merle-Béral From Immunology and Inflammation, Institut Pasteur, Department of Hematology, Pharmacy, Hôpital Pitié-Salpêtrière, Paris, and Radiobiology and Oncology CEA/DRR, Fontenay aux Roses, France. Type 4 phosphodiesterase (PDE4) inhibitors reportedly induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Following clinical improvement of one previously untreated CLL patient with sildenafil therapy, we evaluated the in vitro induction of apoptosis in CLL cells by 4 PDE5/6 inhibitors, including sildenafil, vardenafil, zaprinast, and methoxyquinazoline (MQZ). After 24 hours of culture, the various PDE inhibitors differed in their ability to induce apoptosis, with zaprinast displaying no killing effect. Normal B cells isolated from control donors were totally resistant to PDE-induced apoptosis. Vardenafil was 3 and 30 times more potent an inducer of apoptosis than sildenafil and MQZ, respectively. Both vardenafil and sildenafil failed to elevate adenosine 3'5' cyclic monophosphate (cAMP) levels, largely excluding an inhibitory effect on cAMP-PDE3, -PDE4, and -PDE7. Vardenafil- or sildenafil-treated B-CLL cells displayed up to 30% intracellular active caspase 3. Drug-induced apoptosis was inhibited by the caspase inhibitor z-VAD.fmk, prevented by interleukin-4 (IL-4), and significantly reduced by stromal-derived factor1- (SDF-1). We conclude that vardenafil and sildenafil induce caspase-dependent apoptosis of B-CLL cells in vitro and thus might be considered in the treatment of CLL patients. However, further in vivo investigations should be warranted. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. N. Keswani, K. J. Peyton, W. Durante, A. I. Schafer, and D. A. Tulis The Cyclic GMP Modulators YC-1 and Zaprinast Reduce Vessel Remodeling Through Antiproliferative and Proapoptotic Effects Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2009; 14(2): 116 - 124. [Abstract] [PDF] J. Nagendran and E. D. Michelakis Mitochondrial NOS is upregulated in the hypoxic heart: implications for the function of the hypertrophied right ventricle Am J Physiol Heart Circ Physiol, June 1, 2009; 296(6): H1723 - H1726. [Full Text] [PDF] P. Serafini, K. Meckel, M. Kelso, K. Noonan, J. Califano, W. Koch, L. Dolcetti, V. Bronte, and I. Borrello Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function J. Exp. Med., November 27, 2006; 203(12): 2691 - 2702. [Abstract] [Full Text] [PDF] K. W. Yip, X. Mao, P.Y. B. Au, D. W. Hedley, S. Chow, S. Dalili, J. D. Mocanu, C. Bastianutto, A. Schimmer, and F.-F. Liu Benzethonium Chloride: A Novel Anticancer Agent Identified by Using a Cell-Based Small-Molecule Screen. Clin. Cancer Res., September 15, 2006; 12(18): 5557 - 5569. [Abstract] [Full Text] [PDF] A. Das, L. Xi, and R. C. Kukreja Phosphodiesterase-5 Inhibitor Sildenafil Preconditions Adult Cardiac Myocytes against Necrosis and Apoptosis: ESSENTIAL ROLE OF NITRIC OXIDE SIGNALING J. Biol. Chem., April 1, 2005; 280(13): 12944 - 12955. [Abstract] [Full Text] [PDF] D. T. Jones, E. Addison, J. M. North, M. W. Lowdell, A. V. Hoffbrand, A. B. Mehta, K. Ganeshaguru, N. I. Folarin, and R. G. Wickremasinghe Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs Blood, March 1, 2004; 103(5): 1855 - 1861. [Abstract] [Full Text] [PDF]

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