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In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin
AuthorHohenegger, Martin ; Werner, Martin ; Bardy, Johanna ; Berger-Sieczkowski, Evelyn ; Atil, Bihter
Published in
Naunyn-Schmiedeberg's Archives of Pharmacology, New York, 2016, Vol. 389, Issue 1, page 17-32
PublishedNew York : Springer, 2016
Document typeJournal Article
Keywords (EN)abc-transporter / apoptosis / dolichol / glycosylation / hmg-coa reductase inhibitors / neuroblastoma / rhabdomyosarcoma / human rhabdomyosarcoma cells / human p-glycoprotein / multidrug-resistance / endoplasmic-reticulum / drug-resistance / n-glycosylation / abc transporters / cancer-cells / muscle-cells / human mdr1
Project-/ReportnumberP 22385-B11
URNurn:nbn:at:at-ubmuw:3-1593 Persistent Identifier (URN)
 The work is publicly available
In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin [1.05 mb]
Abstract (English)

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.

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