Abstract
p53 is a key regulator in cell apoptosis, and cancer cells deficient in p53 expression fail to respond to chemotherapy. Here we show that effective Doxorubicin (DOX)-induced apoptosis is p53-dependent. However, an alternative treatment of DOX/TNF-alpha/DOX restored sensitivity of p53-deficient cells to DOX-induced apoptosis. Treatment of cells with TNF-alpha resulted in a decrease of p21 (waf1/cip1/sdi1) expression following second dose of DOX. In previous work, we demonstrated that p21 suppressed DOX-induced apoptosis via its (cyclin-dependent kinase) CDK-binding and CDK-inhibitory activity. Thus, we propose that TNF-alpha enhances the anti-cancer effect of DOX through suppressing the anti-apoptotic activity of p21, and that a combined treatment TNF-alpha/Dox is an effective chemotherapeutic strategy for p53-deficient cancers.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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CDC2-CDC28 Kinases / metabolism
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / biosynthesis
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Cell Line, Tumor
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Down-Regulation
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm
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Drug Synergism
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Gene Expression Regulation, Neoplastic
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Humans
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NF-kappa B / metabolism
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha / pharmacology*
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Tumor Suppressor Protein p53 / biosynthesis*
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Tumor Suppressor Protein p53 / genetics
Substances
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Antineoplastic Agents
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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NF-kappa B
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53
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Doxorubicin
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2