Abstract
Inhibitors of topoisomerase I, such as camptothecin, have proven to be among the most promising new classes of anti-neoplastic agents introduced into the clinical setting in recent years. Irinotecan (CPT-11) is one of the most widely used camptothecin analogs and is converted to form the active metabolite SN-38. The present study was designed to explore apoptosis induced by SN38 and anti-Fas antibody (CH11) in WR/Fas-SMS1 cells and its possible mechanisms. The results demonstrate that combination of SN38 and CH11 synergistically enhanced cell apoptosis in WR/Fas-SMS1 cells. Western blotting analysis showed that combination of SN38 and CH11 activated the ATM-Chk1-p53 pathway, increased protein expression of phospho-p53 and cleavaged caspase-3, but down-regulated expression of phospho-p21. Our data suggest that combination of SN38 and CH11 enhanced apoptosis through down-regulation of p21 phosphorylation. In conclusion, inhibition of p21 could be a new adjuvant approach in cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Apoptosis / drug effects
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Ataxia Telangiectasia Mutated Proteins
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Camptothecin / analogs & derivatives*
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Camptothecin / pharmacology
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Caspase 3 / metabolism
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Checkpoint Kinase 1
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DNA-Binding Proteins / metabolism
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Drug Synergism
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Enzyme Activation / drug effects
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Humans
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Irinotecan
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Lymphoma, T-Cell / drug therapy
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Lymphoma, T-Cell / enzymology
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Lymphoma, T-Cell / immunology
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Lymphoma, T-Cell / pathology
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Mice
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Topoisomerase I Inhibitors / pharmacology*
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Tumor Suppressor Protein p53 / metabolism
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Tumor Suppressor Proteins / metabolism
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fas Receptor / genetics
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fas Receptor / immunology*
Substances
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Antibodies, Monoclonal
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Cell Cycle Proteins
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DNA-Binding Proteins
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Topoisomerase I Inhibitors
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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fas Receptor
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Irinotecan
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Protein Kinases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Protein Serine-Threonine Kinases
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Caspase 3
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Camptothecin