Abstract
NO (nitric oxide) donating drugs have been investigated for their important role in the sensitization of neoplastic cells to chemotherapy drugs. The goal of this work was to investigate the involvement of NO in the resistance of K562 cells to DNR (daunorubicin). Only simultaneous addition of DNR and SNAP (S-nitroso-N-acetyl-dl-penicillamine) caused significant cell death by apoptosis. Combination of the compounds decreased Bcl-2 and survivin, and increased Bax and active-caspase 3 expression. Fluorescence microscope and cytometric analysis showed that DNR and SNAP together caused DNR intracellular accumulation in K562 cells. RT-PCR (reverse transcription-PCR) analysis showed that DNR and SNAP, alone or in association, produced significant decreases in lrp expression. abcc1 gene expression was unaffected by the presence of SNAP, but when treated with DNR there was a small reduction that was intensified by DNR and SNAP in combination. The transport mechanism involved in the resistance to DNR in K562 cells involves ABCC1 and LRP (lung resistance protein) resistance proteins. DNR and SNAP inhibition of the expression of these proteins occurs by distinct mechanisms, and this disrupts the K562 resistance to DNR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibiotics, Antineoplastic / metabolism*
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Antibiotics, Antineoplastic / pharmacology
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Apoptosis Regulatory Proteins / metabolism
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cell Shape / drug effects
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Cell Survival / drug effects
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Daunorubicin / metabolism*
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Daunorubicin / pharmacology
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Drug Resistance, Neoplasm
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Drug Synergism
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Humans
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Inhibitor of Apoptosis Proteins / metabolism
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Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
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Multidrug Resistance-Associated Proteins / metabolism
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Nitric Oxide / pharmacology*
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Nitric Oxide Donors / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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S-Nitroso-N-Acetylpenicillamine / pharmacology*
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Survivin
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bcl-2-Associated X Protein / metabolism
Substances
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Antibiotics, Antineoplastic
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Apoptosis Regulatory Proteins
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BAX protein, human
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BIRC5 protein, human
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Inhibitor of Apoptosis Proteins
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LRP1 protein, human
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Low Density Lipoprotein Receptor-Related Protein-1
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Multidrug Resistance-Associated Proteins
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Nitric Oxide Donors
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Proto-Oncogene Proteins c-bcl-2
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Survivin
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bcl-2-Associated X Protein
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Nitric Oxide
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S-Nitroso-N-Acetylpenicillamine
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CASP3 protein, human
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Caspase 3
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multidrug resistance-associated protein 1
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Daunorubicin