Abstract
The enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, involved in de novo cholesterol synthesis and cell-cycle progression, was identified as a potential mediator of the growth inhibitory effects of retinoic acid on human neuroblastoma. Lovastatin, a nonreversible inhibitor of HMG-CoA reductase, induced extensive cytotoxicity that was restricted to drug-resistant P-glycoprotein-expressing neuroblastoma cell lines. This response was potentiated by dibutyryl cyclic AMP but not retinoic acid. Patients with advanced-stage metastatic neuroblastoma often display an acquired chemoresistant phenotype, which may in part be mediated by P-glycoprotein. Our studies support the application or use of HMG-CoA reductase inhibitors as potential therapeutic agents in the treatment of these patients who are refractory to chemotherapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Base Sequence
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Bucladesine / pharmacology
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DNA Primers / genetics
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Enzyme Inhibitors / pharmacology*
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Hydroxymethylglutaryl CoA Reductases / genetics
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Hydroxymethylglutaryl CoA Reductases / metabolism*
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Hydroxymethylglutaryl-CoA Reductase Inhibitors*
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Lovastatin / pharmacology*
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Molecular Sequence Data
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Neuroblastoma / drug therapy
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Neuroblastoma / genetics
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Neuroblastoma / metabolism*
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Tretinoin / pharmacology*
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Tumor Cells, Cultured
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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DNA Primers
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Enzyme Inhibitors
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Tretinoin
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Bucladesine
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Lovastatin
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Hydroxymethylglutaryl CoA Reductases