Abstract
The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been shown to induce apoptosis in various tumor cell lines including human non-small cell lung carcinoma (NSCLC) cells, which are resistant to the natural all-trans retinoic acid and to many synthetic receptor-selective retinoids. Although the mechanism of this effect was not elucidated, it was found to be independent of nuclear retinoid receptors. In the present study, we analysed the mechanisms by which CD437 induces apoptosis in two human NSCLC cell lines: H460 with wild-type p53 and H1792 with mutant p53. Both cell lines underwent apoptosis after exposure to CD437, although the cell line with wild-type p53 (H460) was more sensitive to the induction of apoptosis. CD437 increased the activity of caspase in both cell lines, however, the effect was much more pronounced in the H460 cells. The caspase inhibitors (Z-DEVD-FMK and Z-VAD-FMK) suppressed CD437-induced CPP32-like caspase activation and apoptosis in both cell lines. CD437 induced the expression of the p53 gene and its target genes, p21, Bax, and Killer/DR5, only in the H460 cells. These results suggest that CD437-induced apoptosis is more extensive in NSCLC cells that express wild-type p53, possibly due to the involvement of the p53 regulated genes Killer/DR5, and Bax although CD437 can also induce apoptosis by means of a p53-independent mechanism. Both pathways of CD437-induced apoptosis appear to involve activation of CPP32-like caspase.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / pathology
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Amino Acid Chloromethyl Ketones / pharmacology
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Carcinoma, Large Cell / genetics
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Carcinoma, Large Cell / pathology
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Carcinoma, Non-Small-Cell Lung / pathology*
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Caspase 3
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Caspase Inhibitors
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Cell Cycle / drug effects
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / biosynthesis
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Cyclins / genetics
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Cysteine Proteinase Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, bcl-2
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Humans
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Lung Neoplasms / pathology*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Oligopeptides / pharmacology
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Retinoids / pharmacology*
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / pathology
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bcl-2-Associated X Protein
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bcl-X Protein
Substances
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Amino Acid Chloromethyl Ketones
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Antineoplastic Agents
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BAX protein, human
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BCL2L1 protein, human
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CD 437
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CDKN1A protein, human
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Caspase Inhibitors
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Cysteine Proteinase Inhibitors
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Neoplasm Proteins
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Oligopeptides
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Retinoids
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bcl-2-Associated X Protein
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bcl-X Protein
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benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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CASP3 protein, human
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Caspase 3