In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin

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• 作者：Bihter Atil ; Evelyn Berger-Sieczkowski…
• 关键词：ABC ; transporter ; Apoptosis ; Dolichol ; Glycosylation ; HMG ; CoA reductase inhibitors ; Neuroblastoma ; Rhabdomyosarcoma
• 刊名：Naunyn-Schmiedeberg's Archives of Pharmacology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：389
• 期：1
• 页码：17-32
• 全文大小：1,080 KB
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• 作者单位：Bihter Atil (1)
  Evelyn Berger-Sieczkowski (2)
  Johanna Bardy (1) (3)
  Martin Werner (1) (3)
  Martin Hohenegger (1)
  
  1. Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria
  2. Department of Neurology, Medical University of Vienna, Vienna, Austria
  3. Department of Internal Medicine, Hanuschkrankenhaus, Heinrich-Collin-Strasse 30, 1140, Vienna, Austria
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Pharmacology and Toxicology
  Neurosciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1912

文摘

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. Keywords ABC-transporter Apoptosis Dolichol Glycosylation HMG-CoA reductase inhibitors Neuroblastoma Rhabdomyosarcoma