title: Antimalarial exposure delays Plasmodium falciparum intra-erythrocytic cycle and drives drug transporter genes expression.
abstract: 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.
  
  
  RESULTS
  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
  Both cell cycle delay and induced gene expression represent potentially important mechanisms for parasites to escape the effect of the antimalarial drug.
authors.affiliation: Malaria Research Lab, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. isabel.veiga@ki.se
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Veiga
authors.forename: Pedro Eduardo
authors.initials: PE
authors.lastname: Ferreira
authors.forename: Berit Aydin
authors.initials: BA
authors.lastname: Schmidt
authors.forename: Ulf
authors.initials: U
authors.lastname: Ribacke
authors.forename: Anders
authors.initials: A
authors.lastname: Björkman
authors.forename: Ales
authors.initials: A
authors.lastname: Tichopad
authors.forename: José Pedro
authors.initials: JP
authors.lastname: Gil
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects*; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000166:cytology* / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D015767:Mefloquine / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics*; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects* / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D026901:Membrane Transport Proteins; D015800:Protozoan Proteins; D012333:RNA, Messenger; C031327:artemisinin; D015767:Mefloquine
references.citation: Antimicrob Agents Chemother. 2002 Apr;46(4):958-65
references.pmid: 11897575
references.citation: Trends Parasitol. 2007 Jul;23(7):332-9
references.pmid: 17493873
references.citation: Am J Trop Med Hyg. 2006 Aug;75(2):212-8
references.pmid: 16896121
references.citation: PLoS Pathog. 2010 May 13;6(5):e1000887
references.pmid: 20485514
references.citation: Exp Parasitol. 2007 Sep;117(1):87-92
references.pmid: 17475254
references.citation: Clin Infect Dis. 2006 Jun 1;42(11):1570-7
references.pmid: 16652314
references.citation: Science. 2002 Oct 4;298(5591):210-3
references.pmid: 12364805
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D539-43
references.pmid: 18957442
references.citation: Lancet. 2004 Jul 31-Aug 6;364(9432):438-447
references.pmid: 15288742
references.citation: Clin Chem. 2003 Jan;49(1):51-9
references.pmid: 12507960
references.citation: Antimicrob Agents Chemother. 2005 Aug;49(8):3575-7
references.pmid: 16048989
references.citation: N Engl J Med. 2009 Jul 30;361(5):455-67
references.pmid: 19641202
references.citation: PLoS Med. 2007 Nov 6;4(11):e309
references.pmid: 17988171
references.citation: Antimicrob Agents Chemother. 2008 Apr;52(4):1438-45
references.pmid: 18195056
references.citation: PLoS Biol. 2003 Oct;1(1):E5
references.pmid: 12929205
references.citation: Science. 1989 Jun 9;244(4909):1184-6
references.pmid: 2658061
references.citation: Mol Microbiol. 2003 Aug;49(4):977-89
references.pmid: 12890022
references.citation: Exp Parasitol. 1995 Dec;81(4):556-63
references.pmid: 8542997
references.citation: J Infect Dis. 2010 Feb 15;201(4):570-9
references.pmid: 20085495
references.citation: Malar J. 2002 Oct 14;1:12
references.pmid: 12423551
references.citation: Malar J. 2005 Mar 18;4:17
references.pmid: 15774020
references.citation: N Engl J Med. 2008 Dec 11;359(24):2619-20
references.pmid: 19064625
references.citation: Mol Cell. 2004 Sep 24;15(6):867-77
references.pmid: 15383277
references.citation: Trans R Soc Trop Med Hyg. 2005 Jan;99(1):62-70
references.pmid: 15550263
references.citation: Genome Biol. 2005;6(3):R26
references.pmid: 15774027
references.citation: Mol Microbiol. 2003 Aug;49(3):671-83
references.pmid: 12864851
references.citation: Cancer Res. 2003 Jun 1;63(11):2705-15
references.pmid: 12782571
references.citation: Mol Biochem Parasitol. 2009 Oct;167(2):81-94
references.pmid: 19464325
references.citation: Nature. 2000 Feb 24;403(6772):906-9
references.pmid: 10706290
references.citation: EMBO J. 2005 Jul 6;24(13):2294-305
references.pmid: 15944738
references.citation: Mol Microbiol. 2005 Aug;57(4):913-26
references.pmid: 16091034
references.citation: Biochem Biophys Res Commun. 2004 Aug 13;321(1):197-201
references.pmid: 15358235
references.citation: EMBO J. 1992 Aug;11(8):3067-75
references.pmid: 1353446
references.citation: EMBO J. 2006 Jul 12;25(13):3000-11
references.pmid: 16794577
references.citation: PLoS Pathog. 2008 Nov;4(11):e1000214
references.pmid: 19023412
references.citation: Int J Cancer. 2009 Feb 15;124(4):991-7
references.pmid: 19048622
references.citation: Semin Cell Biol. 1993 Feb;4(1):29-35
references.pmid: 8095826
references.citation: Science. 1976 Aug 20;193(4254):673-5
references.pmid: 781840
references.citation: Science. 2009 Sep 25;325(5948):1680-2
references.pmid: 19779197
references.citation: J Infect Dis. 2006 Aug 15;194(4):528-35
references.pmid: 16845638