title: Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis.
abstract: BACKGROUND
  Leishmaniasis, a parasitic disease caused by protozoa of the genus Leishmania, affects more than 12 million people worldwide. Quercetin has generated considerable interest as a pharmaceutical compound with a wide range of therapeutic activities. One such activity is exhibited against the bloodstream parasite Trypanosoma brucei and amastigotes of Leishmania donovani. However, the mechanism of protozoan action of quercetin has not been studied.
  
  
  RESULTS
  In the present study, we report here the mechanism for the antileishmanial activity of quercetin against Leishmania amazonensis promastigotes. Quercetin inhibited L. amazonensis promastigote growth in a dose- and time- dependent manner beginning at 48 hours of treatment and with maximum growth inhibition observed at 96 hours. The IC(50) for quercetin at 48 hours was 31.4 µM. Quercetin increased ROS generation in a dose-dependent manner after 48 hours of treatment. The antioxidant GSH and NAC each significantly reduced quercetin-induced cell death. In addition, quercetin caused mitochondrial dysfunction due to collapse of mitochondrial membrane potential.
  
  
  CONCLUSIONS
  The effects of several drugs that interfere directly with mitochondrial physiology in parasites such as Leishmania have been described. The unique mitochondrial features of Leishmania make this organelle an ideal drug target while minimizing toxicity. Quercetin has been described as a pro-oxidant, generating ROS which are responsible for cell death in some cancer cells. Mitochondrial membrane potential loss can be brought about by ROS added directly in vitro or induced by chemical agents. Taken together, our results demonstrate that quercetin eventually exerts its antileishmanial effect on L. amazonensis promastigotes due to the generation of ROS and disrupted parasite mitochondrial function.
authors.affiliation: Laboratório de Bioquímica de Tripanosomatideos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Fonseca-Silva
authors.forename: Job D F
authors.initials: JD
authors.lastname: Inacio
authors.forename: Marilene M
authors.initials: MM
authors.lastname: Canto-Cavalheiro
authors.forename: Elmo Eduardo
authors.initials: EE
authors.lastname: Almeida-Amaral
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007891:Leishmania / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000981:Antiprotozoal Agents; D017382:Reactive Oxygen Species; D011794:Quercetin