title: Clomipramine kills Trypanosoma brucei by apoptosis.
abstract: Drug repositioning, i.e. use of existing medicals to treat a different illness, is especially rewarding for neglected tropical diseases (NTD), since in this field the pharmaceutical industry is rather reluctant to spend vast investments for drug development. NTDs afflict primarily poor populations in under-developed countries, which minimizes financial profit. Here we investigated the trypanocidal effect of clomipramine, a commercial antipsychotic drug, on Trypanosoma brucei. The data showed that this drug killed the parasite with an IC50 of about 5μM. Analysis of the involved cell death mechanism revealed furthermore an initial autophagic stress response and finally the induction of apoptosis. The latter was substantiated by a set of respective markers such as phosphatidylserine exposition, DNA degradation, loss of the inner mitochondrial membrane potential and characteristic morphological changes. Clomipramine was described as a trypanothione inhibitor, but as judged from our results it also showed DNA binding capacities and induced substantial morphological changes. We thus consider it likely that the drug induces a multifold adverse interaction with the parasite's physiology and induces stress in a way that trypanosomes cannot cope with.
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas-Biologia Celular e Molecular, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá-PR, Brazil; Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.
authors.forename: Jean Henrique
authors.initials: JH
authors.lastname: de Silva Rodrigues
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Stein
authors.affiliation: Facultad de Ciencias Médicas, Universidade Nacional de Córdoba, Cordoba, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Strauss
authors.affiliation: Facultad de Ciencias Médicas, Universidade Nacional de Córdoba, Cordoba, Argentina.
authors.forename: Héctor Walter
authors.initials: HW
authors.lastname: Rivarola
authors.affiliation: Departamento de Ciências Básicas da Saúde, Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá-PR, Brazil.
authors.forename: Tânia
authors.initials: T
authors.lastname: Ueda-Nakamura
authors.affiliation: Programa de Pós-Graduação em Ciências Biológicas-Biologia Celular e Molecular, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá-PR, Brazil; Departamento de Ciências Básicas da Saúde, Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá-PR, Brazil.
authors.forename: Celso Vataru
authors.initials: CV
authors.lastname: Nakamura
authors.affiliation: Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany. Electronic address: michael.duszenko@uni-tuebingen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Duszenko
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002997:Clomipramine / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D002997:Clomipramine
keywords: Apoptosis; Clomipramine; Sleeping sickness