title: Natural sesquiterpene lactones induce programmed cell death in Trypanosoma cruzi: a new therapeutic target?
abstract: BACKGROUND
  Chagas disease or American Trypanosomiasis is caused by the flagellated protozoan parasite Trypanosoma cruzi (T. cruzi) and is recognized by the WHO as one of the world's 17 neglected tropical diseases. Only two drugs (Benznidazol, Bz and Nifurtimox, Nx) are currently accepted for treatment, however they cause severe adverse effects and their efficacy is still controversial. It is then important to explore for new drugs.
  
  
  OBJECTIVE
  Programmed cell death (PCD) in parasites offers interesting new therapeutic targets. The aim of this work was to evaluate the induction of PCD in T. cruzi by two natural sesquiterpene lactones (STLs), dehydroleucodine (DhL) and helenalin (Hln) as compared with the two conventional drugs, Bz and Nx.
  
  
  METHODS
  Hln and DhL were isolated from aerial parts of Gaillardia megapotamica and Artemisia douglassiana Besser, respectively. Purity of compounds (greater than 95%) was confirmed by (13)C-nuclear magnetic resonance, melting point analysis, and optical rotation. Induction of PCD in T. cruzi epimastigotes and trypomastigotes by DhL, Hln, Bz and Nx was assayed by phosphatidylserine exposure at the parasite surface and by detection of DNA fragmentation using the TUNEL assay. Trypanocidal activity of natural and synthetic compounds was assayed by measuring parasite viability using the MTT method.
  
  
  RESULTS
  The two natural STLs, DhL and Hln, induce programmed cell death in both, the replicative epimastigote form and the infective trypomastigote form of T. cruzi. Interestingly, the two conventional antichagasic drugs (Bz and Nx) do not induce programmed cell death. A combination of DhL and either Bz or Nx showed an increased effect of natural compounds and synthetic drugs on the decrease of parasite viability.
  
  
  CONCLUSIONS
  DhL and Hln induce programmed cell death in T. cruzi replicative epimastigote and infective trypomastigote forms, which is a different mechanism of action than the conventional drugs to kill the parasite. Therefore DhL and Hln may offer an interesting option for the treatment of Chagas disease, alone or in combination with conventional drugs.
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: V
authors.initials: V
authors.lastname: Jimenez
authors.affiliation: Programa de Anatomía y Biología del Desarrollo, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: U
authors.initials: U
authors.lastname: Kemmerling
authors.affiliation: Laboratorio de Salud de Ecosistemas, Escuela de Medicina Veterinaria, Facultad de Ecología y Recursos Naturales, Universidad Andrés Bello, Santiago, Chile.
authors.forename: R
authors.initials: R
authors.lastname: Paredes
authors.affiliation: Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Chile.
authors.forename: J D
authors.initials: JD
authors.lastname: Maya
authors.affiliation: Instituto de Histología y Embriología, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina.
authors.forename: M A
authors.initials: MA
authors.lastname: Sosa
authors.affiliation: Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile. Electronic address: ngalanti@med.uchile.cl.
authors.forename: N
authors.initials: N
authors.lastname: Galanti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019306:Artemisia / Q000737:chemistry; D002522:Chlorocebus aethiops; D007783:Lactones / Q000494:pharmacology*; D015394:Molecular Structure; D009547:Nifurtimox / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells
chemical_list: D007783:Lactones; D009593:Nitroimidazoles; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; D014344:Trypanocidal Agents; C079949:dehydroleucodine; C001329:helenalin; D009547:Nifurtimox; C009999:benzonidazole
keywords: Chagas disease; Programmed cell death; Sesquiterpene lactones; Trypanosoma cruzi