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Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression

Detalhes bibliográficos
Autor(a) principal: Isabel Veiga, Maria
Data de Publicação: 2010
Outros Autores: Ferreira, Pedro, Schmidt, Berit Aydin, Ribacke, Ulf, Bjorkman, Anders, Tichopad, Ales, Gil, José Pedro
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.1/11192
Resumo: Background: Multi-drug resistant Plasmodium falciparum is a major obstacle to malaria control and is emerging as a complex phenomenon. Mechanisms of drug evasion based on the intracellular extrusion of the drug and/or modification of target proteins have been described. However, cellular mechanisms related with metabolic activity have also been seen in eukaryotic systems, e. g. cancer cells. Recent observations suggest that such mechanism may occur in P. falciparum. Methodology/Principal Findings: We therefore investigated the effect of mefloquine exposure on the cell cycle of three P. falciparum clones (3D7, FCB, W2) with different drug susceptibilities, while investigating in parallel the expression of four genes coding for confirmed and putative drug transporters (pfcrt, pfmdr1, pfmrp1 and pfmrp2). Mefloquine induced a previously not described dose and clone dependent delay in the intra-erythrocytic cycle of the parasite. Drug impact on cell cycle progression and gene expression was then merged using a non-linear regression model to determine specific drug driven expression. This revealed a mild, but significant, mefloquine driven gene induction up to 1.5 fold. Conclusions/Significance: Both cell cycle delay and induced gene expression represent potentially important mechanisms for parasites to escape the effect of the antimalarial drug.
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spelling Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes ExpressionChloroquine resistanceMalaria parasitesCopy numberPfmdr1 GeneIn-VitroArtemisininSensitivityMefloquinePfcrtRecrudescenceBackground: Multi-drug resistant Plasmodium falciparum is a major obstacle to malaria control and is emerging as a complex phenomenon. Mechanisms of drug evasion based on the intracellular extrusion of the drug and/or modification of target proteins have been described. However, cellular mechanisms related with metabolic activity have also been seen in eukaryotic systems, e. g. cancer cells. Recent observations suggest that such mechanism may occur in P. falciparum. Methodology/Principal Findings: We therefore investigated the effect of mefloquine exposure on the cell cycle of three P. falciparum clones (3D7, FCB, W2) with different drug susceptibilities, while investigating in parallel the expression of four genes coding for confirmed and putative drug transporters (pfcrt, pfmdr1, pfmrp1 and pfmrp2). Mefloquine induced a previously not described dose and clone dependent delay in the intra-erythrocytic cycle of the parasite. Drug impact on cell cycle progression and gene expression was then merged using a non-linear regression model to determine specific drug driven expression. This revealed a mild, but significant, mefloquine driven gene induction up to 1.5 fold. Conclusions/Significance: Both cell cycle delay and induced gene expression represent potentially important mechanisms for parasites to escape the effect of the antimalarial drug.Swedish Development Cooperation Agency - Department for Research Cooperation [SWE 2005 - 0017, SWE 2005 - 4596, SWE-2007-174, SWE-2005-4027]; Fundacao para a Ciencia e Tecnologia (FCT)/Ministerio da Ciencia e Ensino Superior, Portugal - MCES [SFRH/BD/28393/2006, SFRH/BD/28368/2006]Public Library of ScienceSapientiaIsabel Veiga, MariaFerreira, PedroSchmidt, Berit AydinRibacke, UlfBjorkman, AndersTichopad, AlesGil, José Pedro2018-12-07T14:52:45Z2010-082010-08-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/11192eng1932-620310.1371/journal.pone.0012408info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-07-24T10:22:57Zoai:sapientia.ualg.pt:10400.1/11192Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:02:42.191833Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
title Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
spellingShingle Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
Isabel Veiga, Maria
Chloroquine resistance
Malaria parasites
Copy number
Pfmdr1 Gene
In-Vitro
Artemisinin
Sensitivity
Mefloquine
Pfcrt
Recrudescence
title_short Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
title_full Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
title_fullStr Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
title_full_unstemmed Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
title_sort Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
author Isabel Veiga, Maria
author_facet Isabel Veiga, Maria
Ferreira, Pedro
Schmidt, Berit Aydin
Ribacke, Ulf
Bjorkman, Anders
Tichopad, Ales
Gil, José Pedro
author_role author
author2 Ferreira, Pedro
Schmidt, Berit Aydin
Ribacke, Ulf
Bjorkman, Anders
Tichopad, Ales
Gil, José Pedro
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Sapientia
dc.contributor.author.fl_str_mv Isabel Veiga, Maria
Ferreira, Pedro
Schmidt, Berit Aydin
Ribacke, Ulf
Bjorkman, Anders
Tichopad, Ales
Gil, José Pedro
dc.subject.por.fl_str_mv Chloroquine resistance
Malaria parasites
Copy number
Pfmdr1 Gene
In-Vitro
Artemisinin
Sensitivity
Mefloquine
Pfcrt
Recrudescence
topic Chloroquine resistance
Malaria parasites
Copy number
Pfmdr1 Gene
In-Vitro
Artemisinin
Sensitivity
Mefloquine
Pfcrt
Recrudescence
description Background: Multi-drug resistant Plasmodium falciparum is a major obstacle to malaria control and is emerging as a complex phenomenon. Mechanisms of drug evasion based on the intracellular extrusion of the drug and/or modification of target proteins have been described. However, cellular mechanisms related with metabolic activity have also been seen in eukaryotic systems, e. g. cancer cells. Recent observations suggest that such mechanism may occur in P. falciparum. Methodology/Principal Findings: We therefore investigated the effect of mefloquine exposure on the cell cycle of three P. falciparum clones (3D7, FCB, W2) with different drug susceptibilities, while investigating in parallel the expression of four genes coding for confirmed and putative drug transporters (pfcrt, pfmdr1, pfmrp1 and pfmrp2). Mefloquine induced a previously not described dose and clone dependent delay in the intra-erythrocytic cycle of the parasite. Drug impact on cell cycle progression and gene expression was then merged using a non-linear regression model to determine specific drug driven expression. This revealed a mild, but significant, mefloquine driven gene induction up to 1.5 fold. Conclusions/Significance: Both cell cycle delay and induced gene expression represent potentially important mechanisms for parasites to escape the effect of the antimalarial drug.
publishDate 2010
dc.date.none.fl_str_mv 2010-08
2010-08-01T00:00:00Z
2018-12-07T14:52:45Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.1/11192
url http://hdl.handle.net/10400.1/11192
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1932-6203
10.1371/journal.pone.0012408
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science
publisher.none.fl_str_mv Public Library of Science
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
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