Mitochondrial Dysfunction Induced by N-Butyl-1-(4-Dimethylamino)Phenyl-1,2,3,4-Tetrahydro-β-Carboline-3-Carboxamide Is Required for Cell Death of Trypanosoma cruzi

PLoS One. 2015 Jun 18;10(6):e0130652. doi: 10.1371/journal.pone.0130652. eCollection 2015.

Abstract

Background: Chagas' disease is caused by the protozoan Trypanosoma cruzi and affects thousands of people worldwide. The available treatments are unsatisfactory, and new drugs must be developed. Our group recently reported the trypanocidal activity of the synthetic compound N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxamide (C4), but the mechanism of action of this compound was unclear.

Methodology/principal findings: We investigated the mechanism of action of C4 against epimastigote and trypomastigote forms of T. cruzi. The results showed alterations in mitochondrial membrane potential, alterations in cell membrane integrity, an increase in the formation of reactive oxygen species, phosphatidylserine exposure, a reduction of cell volume, DNA fragmentation, and the formation of lipid inclusions.

Conclusion/significance: These finding suggest that mitochondria are a target of C4, the dysfunction of which can lead to different pathways of cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / chemical synthesis
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology*
  • Carbolines / chemical synthesis
  • Carbolines / chemistry
  • Carbolines / pharmacology*
  • Cell Size / drug effects
  • DNA Fragmentation / drug effects
  • Membrane Potential, Mitochondrial / drug effects
  • Mitochondria / metabolism*
  • Phosphatidylserines / metabolism
  • Reactive Oxygen Species / metabolism
  • Singlet Oxygen / metabolism
  • Trypanocidal Agents / chemical synthesis
  • Trypanocidal Agents / chemistry
  • Trypanocidal Agents / pharmacology*
  • Trypanosoma cruzi / drug effects*
  • Trypanosoma cruzi / metabolism

Substances

  • Aniline Compounds
  • Carbolines
  • N-butyl-1-(4-dimethylamino)phenyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxamide
  • Phosphatidylserines
  • Reactive Oxygen Species
  • Trypanocidal Agents
  • Singlet Oxygen

Grants and funding

This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Financiadora de Estudos e Projetos (FINEP), Programa de Pós-Graduação em Ciências Biológicas and Complexo de Centrais de Apoio a Pesquisa (COMCAP-UEM) da Universidade Estadual de Maringá. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.