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Diverse effects on mitochondrial and nuclear functions elicited by drugs and genetic knockdowns in bloodstream stage

Christal Worthen1, Bryan C Jensen, Marilyn Parsons

  • 1Seattle Biomedical Research Institute, Seattle, Washington, USA.

Plos Neglected Tropical Diseases
|May 11, 2010
PubMed
Abstract

Insights

New drugs are needed to treat human African trypanosomiasis as current treatments face resistance. This study compared how different drugs kill Trypanosoma brucei parasites, revealing varied cellular effects and suggesting proliferation assays for drug development.

Area of Science:

  • Parasitology
  • Drug Discovery
  • Cell Biology

Background:

  • Human African trypanosomiasis treatment options are limited due to drug toxicity and resistance.
  • New drugs targeting Trypanosoma brucei subspecies are urgently needed.
  • Cellular mechanisms of parasite death in the bloodstream stage are poorly understood.

Purpose of the Study:

  • To compare the cellular effects of various death-inducing agents on Trypanosoma brucei bloodstream forms.
  • To identify distinct cellular defects caused by different drug targets.
  • To evaluate the reversibility of drug effects and inform anti-parasitic drug development.

Main Methods:

  • Conducted a side-by-side comparison of six drugs and six RNAi knockdowns targeting different cellular functions.
  • Quantified parasite death using flow cytometry, ethidium homodimer, and esterase staining.
  • Assessed cellular defects including mitochondrial potential, reactive oxygen species, cell cycle, and genome segregation.

Main Results:

  • All tested compounds exhibited static effects at low concentrations and lethal effects at high concentrations.
  • Diverse treatments induced varied cellular phenotypes, including disruptions in mitochondrial function, increased reactive oxygen species, and cell cycle arrest.
  • No evidence of phosphatidylserine exposure (apoptosis marker) was observed; ATP reduction lagged behind cell number decrease.
  • Drug-treated cells displayed significant differences in proliferation capacity post-treatment, indicating varying reversibility.

Conclusions:

  • Parasite responses varied significantly based on the treatment, with no single phenotype reliably predicting post-treatment proliferation.
  • Clonal proliferation assays are recommended for selecting promising anti-trypanosomal compounds for further development.
  • Further research into the genetic/biochemical events triggered by effective compounds may reveal novel death pathways.

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