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Prepublished online as a Blood First Edition Paper on April 24, 2003; DOI 10.1182/blood-2003-01-0178. This Article Full Text (PDF) All Versions of this Article: 2003-01-0178v1 102/4/1490    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 Selleri, C. Articles by Rotoli, B. Search for Related Content PubMed PubMed Citation Articles by Selleri, C. Articles by Rotoli, B. Social Bookmarking                   What's this? Submitted January 21, 2003 Accepted April 15, 2003 Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells Carmine Selleri*, Jaroslaw P Maciejewski, Nunzia Montuori, Patrizia Ricci, Valeria Visconte, Bianca Serio, Luigiana Luciano, and Bruno Rotoli Division of Hematology, Federico II University, Naples, Italy Experimental Hematology Section, Taussig Cancer Center, Cleveland, OH, USA Institute of Experimental Endocrinology and Oncology, National Research Council, Naples, Italy * Corresponding author; email: selleri{at}unina.it. Mechanism of action of farnesyltransferase inhibitors (FTIs) is not fully clarified. We investigated the cytotoxic effects of various FTIs in chronic myeloid leukemia (CML), using LAMA cells and marrow cells from 40 CML patients in chronic phase. FTI-mediated cytotoxic effect was observed in LAMA cells and in 65% of primary CML cells, whereas marrow cells from controls were only weakly affected. Cytotoxic effects were partially related to enhanced apoptosis; however, Fas-receptor (FasR) and Fas-ligand (FasL) expression were not modified by FTIs. Susceptibility to FTI-mediated inhibition did not correlate with FasR/FasL expression in CD34+ CML cells. Moreover, intracellular activation of caspase-1 and caspase-8 were not altered by FTIs, and their blockade did not reverse FTI-toxicity. However, we observed FTI-induced activation of caspase-3, and its inhibition partially reverted FTI-induced apoptosis. FTIs did not modulate bcl2, bclxL and bclxS expression, while they increased inducible nitric oxide (iNOS) mRNA and protein levels resulting in higher NO production. Furthermore, C3 exoenzyme, a Rho inhibitor, significantly increased iNOS expression in CML cells suggesting that FTIs may up-regulate NO formation at least partially through FTI-mediated inhibition of Rho. We conclude that FTIs induce selective apoptosis in CML cells via activation of iNOS and caspase-3. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. T. Efuet and K. Keyomarsi Farnesyl and Geranylgeranyl Transferase Inhibitors Induce G1 Arrest by Targeting the Proteasome Cancer Res., January 15, 2006; 66(2): 1040 - 1051. [Abstract] [Full Text] [PDF] J. Pan and S.-C. J. Yeung Recent Advances in Understanding the Antineoplastic Mechanisms of Farnesyltransferase Inhibitors Cancer Res., October 15, 2005; 65(20): 9109 - 9112. [Abstract] [Full Text] [PDF] J. Pan, M. She, Z.-X. Xu, L. Sun, and S.-C. J. Yeung Farnesyltransferase Inhibitors Induce DNA Damage via Reactive Oxygen Species in Human Cancer Cells Cancer Res., May 1, 2005; 65(9): 3671 - 3681. [Abstract] [Full Text] [PDF]

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