Abstract
The mechanism of action of farnesyltransferase inhibitors (FTIs) has not been 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, intra-cellular activation of caspase-1 and -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, whereas 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Antigens, CD34 / immunology
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Apoptosis / drug effects*
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Bone Marrow Cells / metabolism
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Caspase 3
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Caspase Inhibitors
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Caspases / metabolism
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology*
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Farnesyltranstransferase
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Humans
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K562 Cells
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / enzymology
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Neoplastic Stem Cells / metabolism
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Nitric Oxide / biosynthesis
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase / biosynthesis
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type II
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Messenger / biosynthesis
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fas Receptor / metabolism
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rhoA GTP-Binding Protein / antagonists & inhibitors
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rhoB GTP-Binding Protein / antagonists & inhibitors
Substances
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Antigens, CD34
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Caspase Inhibitors
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Enzyme Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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fas Receptor
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Nitric Oxide
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NOS2 protein, human
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Alkyl and Aryl Transferases
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Farnesyltranstransferase
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Protein Serine-Threonine Kinases
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CASP3 protein, human
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Caspase 3
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Caspases
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rhoA GTP-Binding Protein
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rhoB GTP-Binding Protein