Abstract
The novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) has been recently identified to be a potent inducer of apoptosis in human non-small cell lung carcinoma (NSCLC) cells through a nuclear retinoic acid receptor independent mechanism. To approach the mechanism by which CD437 induces apoptosis in NSCLC cells, we investigated the involvement of c-Myc in CD437-induced apoptosis. CD437 (1 microM) up-regulated the expression of c-Myc and of its downstream target genes ornithine decarboxylase (ODC) and cdc25A in all three NSCLC cell lines (i.e., H460, SK-MES-1 and H1792) used. These effects were correlated with cellular susceptibilities to induction of apoptosis by CD437. Furthermore, CD437-induced apoptosis could be blocked by the ODC inhibitor difluoromethylornithine, the caspase inhibitors Z-VAD FMK and Z-DEVD FMK, and c-Myc antisense oligodeoxynucleotide, respectively. These data indicate that c-Myc gene plays an important role in mediating CD437-induced apoptosis in human NSCLC cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Apoptosis / drug effects*
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Carcinoma, Non-Small-Cell Lung / pathology*
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Cysteine Endopeptidases / physiology
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Cysteine Proteinase Inhibitors / pharmacology
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Eflornithine / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, myc*
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Humans
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Lung Neoplasms / pathology*
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Oligonucleotides, Antisense / pharmacology
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Oligopeptides / pharmacology
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Ornithine Decarboxylase / physiology
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Ornithine Decarboxylase Inhibitors
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Protein Tyrosine Phosphatases / biosynthesis
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Protein Tyrosine Phosphatases / genetics
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Proto-Oncogene Proteins c-myc / physiology*
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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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cdc25 Phosphatases*
Substances
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Amino Acid Chloromethyl Ketones
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CD 437
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Cysteine Proteinase Inhibitors
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Oligonucleotides, Antisense
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Oligopeptides
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Ornithine Decarboxylase Inhibitors
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Proto-Oncogene Proteins c-myc
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Retinoids
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benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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CDC25A protein, human
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Protein Tyrosine Phosphatases
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cdc25 Phosphatases
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Cysteine Endopeptidases
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Ornithine Decarboxylase
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Eflornithine