title: Synergy of Omeprazole and Praziquantel In Vitro Treatment against Schistosoma mansoni Adult Worms.
abstract: BACKGROUND
  Treatment and morbidity control of schistosomiasis relies on a single drug, praziquantel (PZQ), and the selection of resistant worms under repeated treatment is a concern. Therefore, there is a pressing need to understand the molecular effects of PZQ on schistosomes and to investigate alternative or synergistic drugs against schistosomiasis.
  
  
  METHODS
  We used a custom-designed Schistosoma mansoni expression microarray to explore the effects of sublethal doses of PZQ on large-scale gene expression of adult paired males and females and unpaired mature females. We also assessed the efficacy of PZQ, omeprazole (OMP) or their combination against S. mansoni adult worms with a survival in vitro assay.
  
  
  RESULTS
  We identified sets of genes that were affected by PZQ in paired and unpaired mature females, however with opposite gene expression patterns (up-regulated in paired and down-regulated in unpaired mature females), indicating that PZQ effects are heavily influenced by the mating status. We also identified genes that were similarly affected by PZQ in males and females. Functional analyses of gene interaction networks were performed with parasite genes that were differentially expressed upon PZQ treatment, searching for proteins encoded by these genes whose human homologs are targets of different drugs used for other diseases. Based on these results, OMP, a widely prescribed proton pump inhibitor known to target the ATP1A2 gene product, was chosen and tested. Sublethal doses of PZQ combined with OMP significantly increased worm mortality in vitro when compared with PZQ or OMP alone, thus evidencing a synergistic effect.
  
  
  CONCLUSIONS
  Functional analysis of gene interaction networks is an important approach that can point to possible novel synergistic drug candidates. We demonstrated the potential of this strategy by showing that PZQ in combination with OMP displayed increased efficiency against S. mansoni adult worms in vitro when compared with either drug alone.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Giulliana T
authors.initials: GT
authors.lastname: Almeida
authors.affiliation: Genomics and Computational Biology Group, Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Regina C G
authors.initials: RC
authors.lastname: Lage
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Leticia
authors.initials: L
authors.lastname: Anderson
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Venancio
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Helder I
authors.initials: HI
authors.lastname: Nakaya
authors.affiliation: Instituto Butantan, São Paulo, São Paulo, Brazil.
authors.forename: Patrícia A
authors.initials: PA
authors.lastname: Miyasato
authors.affiliation: Instituto Butantan, São Paulo, São Paulo, Brazil.
authors.forename: Henrique K
authors.initials: HK
authors.lastname: Rofatto
authors.affiliation: Genomics and Computational Biology Group, Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Adhemar
authors.initials: A
authors.lastname: Zerlotini
authors.affiliation: Instituto Butantan, São Paulo, São Paulo, Brazil.
authors.forename: Eliana
authors.initials: E
authors.lastname: Nakano
authors.affiliation: Genomics and Computational Biology Group, Centro de Pesquisas René Rachou - FIOCRUZ, Belo Horizonte, Minas Gerais, Brazil; Vale Technology Institute, Belém, Pará, Brazil.
authors.forename: Guilherme
authors.initials: G
authors.lastname: Oliveira
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil; Instituto Butantan, São Paulo, São Paulo, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Verjovski-Almeida
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D018509:DNA, Helminth / Q000737:chemistry / Q000235:genetics; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D008297:Male; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009853:Omeprazole / Q000494:pharmacology*; D011223:Praziquantel / Q000494:pharmacology*; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000502:physiology; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: D000871:Anthelmintics; D018509:DNA, Helminth; D011223:Praziquantel; D009853:Omeprazole