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

Naunyn-Schmiedeberg's Archives of Pharmacology
Bihter AtilMartin Hohenegger

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...Continue Reading

References

Mar 15, 1992·Proceedings of the National Academy of Sciences of the United States of America·K Kuchler, J Thorner
Feb 1, 1990·Nature·J L Goldstein, M S Brown
May 1, 1970·Proceedings of the National Academy of Sciences of the United States of America·N H Behrens, L F Leloir
May 1, 1993·British Journal of Cancer·R KramerI C Summerhayes
Aug 15, 1998·Biochemical and Biophysical Research Communications·C LaezzaM Bifulco
Oct 3, 1999·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·T W Loo, D M Clarke
Dec 21, 2000·Current Atherosclerosis Reports·J A Farmer
Mar 17, 2001·British Journal of Pharmacology·K BogmanJ Drewe
Nov 10, 2001·Arteriosclerosis, Thrombosis, and Vascular Biology·M Takemoto, J K Liao
Mar 21, 2002·Nature Reviews. Cancer·Michael M GottesmanSusan E Bates
Apr 19, 2003·American Journal of Physiology. Gastrointestinal and Liver Physiology·Thomas K LeeNazzareno Ballatori
Oct 1, 1954·Journal of Gerontology·A R TAMPLINF W GLAZIER
Aug 24, 2004·Molecular Pharmacology·Zhigang ZhangJin-Ming Yang
Jan 15, 2005·Biochemical Society Symposium·Paula UrquhartNigel M Hooper
May 26, 2005·The Journal of Pharmacology and Experimental Therapeutics·Julia SacherMartin Hohenegger
Aug 30, 2005·Annual Review of Genomics and Human Genetics·Michael Dean, Tarmo Annilo
Dec 13, 2005·Nature Reviews. Cancer·Marie-France DemierreScott M Lippman
Sep 5, 2006·Cancer Research·Michael J CampbellChristopher C Benz
Sep 26, 2006·Biochimica Et Biophysica Acta·Alice Cristina RodriguesRosario D C Hirata
Feb 27, 2007·Cancer Metastasis Reviews·Robert W RobeySusan E Bates
Apr 13, 2007·Expert Review of Anticancer Therapy·Elizabeth Fox, Susan E Bates
Oct 19, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shannon Reagan-ShawNihal Ahmad
May 7, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Jame AbrahamTito Fojo
Jul 1, 2009·British Journal of Pharmacology·C Minichsdorfer, M Hohenegger
Jan 16, 2010·Nature Reviews. Cancer·Jamie I FletcherMurray D Norris
Mar 2, 2010·Nature Reviews. Drug Discovery·UNKNOWN International Transporter ConsortiumLei Zhang
Dec 4, 2010·Journal of Pharmacological Sciences·Syoko TanakaJunko Kimura
Feb 26, 2011·International Journal of Cancer. Journal International Du Cancer·Carolyn A GoardLinda Z Penn
Mar 9, 2011·Journal of Inherited Metabolic Disease·Vincent Cantagrel, Dirk J Lefeber
Oct 5, 2011·Essays in Biochemistry·Akina TamakiSusan E Bates
Nov 23, 2011·Pharmacological Reviews·Patrizia GazzerroMaurizio Bifulco

❮ Previous
Next ❯

Citations

Oct 11, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Daichiro FujiwaraShozo Nishida
Apr 21, 2018·Scientific Reports·Christine WasingerMartin Hohenegger
Jul 6, 2019·Journal of Cardiovascular Pharmacology·Undurti N Das
Sep 4, 2020·World Journal of Clinical Oncology·Cristina I BarbalataAlina S Porfire
Nov 20, 2020·Stem Cells·Sidse Ehmsen, Henrik J Ditzel
Dec 15, 2020·Investigational New Drugs·Katrin MandaGuido Hildebrandt
May 6, 2020·Toxicology Reports·Colin C AndersonJames R Roede
Nov 11, 2021·Glycoconjugate Journal·Inka BrockhausenJennifer Brockhausen

❮ Previous
Next ❯

Methods Mentioned

BETA
glycosylation
xenograft
protein assay
PCR
FCS
FACS
X-ray
ubiquitination
geranylgeranylation

Software Mentioned

Elite LaChrom
SigmaPlot
Flowing
FL
Solutions
CellQuest
ImageJ

Related Concepts

Related Feeds

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis