title: In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin.
abstract: Extrusion of chemotherapeutics by ATP-binding cassette (ABC) transporters like ABCB1 (P-glycoprotein) represents a crucial mechanism of multidrug resistance in cancer therapy. We have previously shown that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin directly inhibits ABCB1, alters the glycosylation of the transporter, and enhances the intracellular accumulation of doxorubicin with subsequent anti-cancer action. Here, we show that simvastatin reduces endogenous dolichol levels and ABCB1 in human neuroblastoma SH-SY5Y cells. Coapplication with dolichol prevents the downregulation of the ABCB1 transporter. Importantly, dolichol also attenuated simvastatin-induced apoptosis, unmasking involvement of unfolded protein response. Direct monitoring of the fluorescent fusion protein YFP-ABCB1 further confirms concentration-dependent reduction of ABCB1 in HEK293 cells by simvastatin. In simvastatin-treated murine xenografts, ABCB1 was also reduced in the liver and rhabdomyosarcoma but did not reach significance in neuroblastoma. Nevertheless, the in vivo anti-cancer effects of simvastatin are corroborated by increased apoptosis in tumor tissues. These findings provide experimental evidence for usage of simvastatin in novel chemotherapeutic regimens and link dolichol depletion to simvastatin-induced anti-cancer activity.
authors: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria.
authors: Bihter
authors: B
authors: Atil
authors: Department of Neurology, Medical University of Vienna, Vienna, Austria.
authors: Evelyn
authors: E
authors: Berger-Sieczkowski
authors: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria.|Department of Internal Medicine, Hanuschkrankenhaus, Heinrich-Collin-Strasse 30, 1140, Vienna, Austria.
authors: Johanna
authors: J
authors: Bardy
authors: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria.|Department of Internal Medicine, Hanuschkrankenhaus, Heinrich-Collin-Strasse 30, 1140, Vienna, Austria.
authors: Martin
authors: M
authors: Werner
authors: Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria. martin.hohenegger@meduniwien.ac.at.
authors: Martin
authors: M
authors: Hohenegger
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004286:Dolichols / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004286:Dolichols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D053148:Caspase 3
keywords: ABC-transporter; Apoptosis; Dolichol; Glycosylation; HMG-CoA reductase inhibitors; Neuroblastoma; Rhabdomyosarcoma