NF-kB inhibition as a strategy to enhance etoposide-induced apoptosis in K562 cell line.
NF-kB is a transcription factor that mediates antiapoptotic signals in several cancer cell lines. Here we have demonstrated that the cytotoxic drug, Etoposide, activates NF-kB in K562, a chronic myeloid leukemia blast crisis cell line. Treatment with the NF-kB inhibitors MG-132, Bay11-7082, and Resveratrol impedes Etoposide-induced NF-kB activation, rendering K562 sensitive to Etoposide-induced apoptosis. Stable expression of mutant form of IkB-alpha, which retains NF-kB inactive in the cytoplasm of cells, confirmed the data obtained with molecular inhibitors. Both inhibitors and stable expression of SR-IkB are associated with down-modulation of the antiapoptotic protein Bcl-xL, suggesting that the survival pathway activated by Etoposide involves NF-kB-mediated Bcl-xL expression.
Morotti
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Division of Haematology and Internal Medicine, Department of Clinical and Biological Sciences of the University of Turin, Turin, Italy. alessandromorotti@yahoo.it
Cilloni
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Pautasso
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Messa
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Arruga
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Defilippi
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Carturan
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Catalano
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Rosso
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Chiarenza
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Taulli
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Bracco
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Rege-Cambrin
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Gottardi
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Saglio
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D000972:Antineoplastic Agents, Phytogenic / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001752:Blast Crisis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects*; D004357:Drug Synergism; D005047:Etoposide / Q000819:agonists / Q000494:pharmacology* / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051020:bcl-X Protein / Q000096:biosynthesis
D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D020672:I-kappa B Proteins; D016328:NF-kappa B; D051020:bcl-X Protein; D005047:Etoposide