Antimalarial Exposure Delays Plasmodium falciparum Intra-Erythrocytic Cycle and Drives Drug Transporter Genes Expression
Main Author: | |
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Publication Date: | 2010 |
Other Authors: | , , , , , |
Format: | Article |
Language: | eng |
Source: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Download full: | http://hdl.handle.net/10400.1/11192 |
Summary: | 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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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 |
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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 |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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