Continuous quinacrine treatment results in the formation of drug-resistant prions.

Quinacrine is a potent antiprion compound in cell culture models of prion disease but has failed to show efficacy in animal bioassays and human clinical trials. Previous studies demonstrated that quinacrine inefficiently penetrates the blood-brain barrier (BBB), which could contribute to its lack of...

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Autores principales:	Sina Ghaemmaghami, Misol Ahn, Pierre Lessard, Kurt Giles, Giuseppe Legname, Stephen J DeArmond, Stanley B Prusiner
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/fcfbe9ebc1594422855e2fb3b5334f33
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spelling	oai:doaj.org-article:fcfbe9ebc1594422855e2fb3b5334f332021-11-25T05:48:28ZContinuous quinacrine treatment results in the formation of drug-resistant prions.1553-73661553-737410.1371/journal.ppat.1000673https://doaj.org/article/fcfbe9ebc1594422855e2fb3b5334f332009-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19956709/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Quinacrine is a potent antiprion compound in cell culture models of prion disease but has failed to show efficacy in animal bioassays and human clinical trials. Previous studies demonstrated that quinacrine inefficiently penetrates the blood-brain barrier (BBB), which could contribute to its lack of efficacy in vivo. As quinacrine is known to be a substrate for P-glycoprotein multi-drug resistance (MDR) transporters, we circumvented its poor BBB permeability by utilizing MDR(0/0) mice that are deficient in mdr1a and mdr1b genes. Mice treated with 40 mg/kg/day of quinacrine accumulated up to 100 microM of quinacrine in their brains without acute toxicity. PrP(Sc) levels in the brains of prion-inoculated MDR(0/0) mice diminished upon the initiation of quinacrine treatment. However, this reduction was transient and PrP(Sc) levels recovered despite the continuous administration of quinacrine. Treatment with quinacrine did not prolong the survival times of prion-inoculated, wild-type or MDR(0/0) mice compared to untreated mice. A similar phenomenon was observed in cultured differentiated prion-infected neuroblastoma cells: PrP(Sc) levels initially decreased after quinacrine treatment then rapidly recovered after 3 d of continuous treatment. Biochemical characterization of PrP(Sc) that persisted in the brains of quinacrine-treated mice had a lower conformational stability and different immunoaffinities compared to that found in the brains of untreated controls. These physical properties were not maintained upon passage in MDR(0/0) mice. From these data, we propose that quinacrine eliminates a specific subset of PrP(Sc) conformers, resulting in the survival of drug-resistant prion conformations. Transient accumulation of this drug-resistant prion population provides a possible explanation for the lack of in vivo efficacy of quinacrine and other antiprion drugs.Sina GhaemmaghamiMisol AhnPierre LessardKurt GilesGiuseppe LegnameStephen J DeArmondStanley B PrusinerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 11, p e1000673 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Sina Ghaemmaghami Misol Ahn Pierre Lessard Kurt Giles Giuseppe Legname Stephen J DeArmond Stanley B Prusiner Continuous quinacrine treatment results in the formation of drug-resistant prions.
description	Quinacrine is a potent antiprion compound in cell culture models of prion disease but has failed to show efficacy in animal bioassays and human clinical trials. Previous studies demonstrated that quinacrine inefficiently penetrates the blood-brain barrier (BBB), which could contribute to its lack of efficacy in vivo. As quinacrine is known to be a substrate for P-glycoprotein multi-drug resistance (MDR) transporters, we circumvented its poor BBB permeability by utilizing MDR(0/0) mice that are deficient in mdr1a and mdr1b genes. Mice treated with 40 mg/kg/day of quinacrine accumulated up to 100 microM of quinacrine in their brains without acute toxicity. PrP(Sc) levels in the brains of prion-inoculated MDR(0/0) mice diminished upon the initiation of quinacrine treatment. However, this reduction was transient and PrP(Sc) levels recovered despite the continuous administration of quinacrine. Treatment with quinacrine did not prolong the survival times of prion-inoculated, wild-type or MDR(0/0) mice compared to untreated mice. A similar phenomenon was observed in cultured differentiated prion-infected neuroblastoma cells: PrP(Sc) levels initially decreased after quinacrine treatment then rapidly recovered after 3 d of continuous treatment. Biochemical characterization of PrP(Sc) that persisted in the brains of quinacrine-treated mice had a lower conformational stability and different immunoaffinities compared to that found in the brains of untreated controls. These physical properties were not maintained upon passage in MDR(0/0) mice. From these data, we propose that quinacrine eliminates a specific subset of PrP(Sc) conformers, resulting in the survival of drug-resistant prion conformations. Transient accumulation of this drug-resistant prion population provides a possible explanation for the lack of in vivo efficacy of quinacrine and other antiprion drugs.
format	article
author	Sina Ghaemmaghami Misol Ahn Pierre Lessard Kurt Giles Giuseppe Legname Stephen J DeArmond Stanley B Prusiner
author_facet	Sina Ghaemmaghami Misol Ahn Pierre Lessard Kurt Giles Giuseppe Legname Stephen J DeArmond Stanley B Prusiner
author_sort	Sina Ghaemmaghami
title	Continuous quinacrine treatment results in the formation of drug-resistant prions.
title_short	Continuous quinacrine treatment results in the formation of drug-resistant prions.
title_full	Continuous quinacrine treatment results in the formation of drug-resistant prions.
title_fullStr	Continuous quinacrine treatment results in the formation of drug-resistant prions.
title_full_unstemmed	Continuous quinacrine treatment results in the formation of drug-resistant prions.
title_sort	continuous quinacrine treatment results in the formation of drug-resistant prions.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/fcfbe9ebc1594422855e2fb3b5334f33
work_keys_str_mv	AT sinaghaemmaghami continuousquinacrinetreatmentresultsintheformationofdrugresistantprions AT misolahn continuousquinacrinetreatmentresultsintheformationofdrugresistantprions AT pierrelessard continuousquinacrinetreatmentresultsintheformationofdrugresistantprions AT kurtgiles continuousquinacrinetreatmentresultsintheformationofdrugresistantprions AT giuseppelegname continuousquinacrinetreatmentresultsintheformationofdrugresistantprions AT stephenjdearmond continuousquinacrinetreatmentresultsintheformationofdrugresistantprions AT stanleybprusiner continuousquinacrinetreatmentresultsintheformationofdrugresistantprions
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Continuous quinacrine treatment results in the formation of drug-resistant prions.

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