HMG–CoA reductase mediates the biological effects of retinoic acid on human neuroblastoma cells: Lovastatin specifically targets P–glycoprotein–expressing cells

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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.