title: A domino effect in drug action: from metabolic assault towards parasite differentiation.
abstract: Awareness is growing that drug target validation should involve systems analysis of cellular networks. There is less appreciation, though, that the composition of networks may change in response to drugs. If the response is homeostatic (e.g. through upregulation of the target protein), this may neutralize the inhibitory effect. In this scenario the effect on cell growth and survival would be less than anticipated based on affinity of the drug for its target. Glycolysis is the sole free-energy source for the deadly parasite Trypanosoma brucei and is therefore a possible target pathway for anti-trypanosomal drugs. Plasma-membrane glucose transport exerts high control over trypanosome glycolysis and hence the transporter is a promising drug target. Here we show that at high inhibitor concentrations, inhibition of trypanosome glucose transport causes cell death. Most interestingly, sublethal concentrations initiate a domino effect in which network adaptations enhance inhibition. This happens via (i) metabolic control exerted by the target protein, (ii) decreases in mRNAs encoding the target protein and other proteins in the same pathway, and (iii) partial differentiation of the cells leading to (low) expression of immunogenic insect-stage coat proteins. We discuss how these 'anti-homeostatic' responses together may facilitate killing of parasites at an acceptable drug dosage.
authors.affiliation: Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, NL-1081 HV Amsterdam, the Netherlands.
authors.forename: Jurgen R
authors.initials: JR
authors.lastname: Haanstra
authors.forename: Eduard J
authors.initials: EJ
authors.lastname: Kerkhoven
authors.forename: Arjen
authors.initials: A
authors.lastname: van Tuijl
authors.forename: Marjolein
authors.initials: M
authors.lastname: Blits
authors.forename: Martin
authors.initials: M
authors.lastname: Wurst
authors.forename: Rick
authors.initials: R
authors.lastname: van Nuland
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Albert
authors.forename: Paul A M
authors.initials: PA
authors.lastname: Michels
authors.forename: Jildau
authors.initials: J
authors.lastname: Bouwman
authors.forename: Christine
authors.initials: C
authors.lastname: Clayton
authors.forename: Hans V
authors.initials: HV
authors.lastname: Westerhoff
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Bakker
mesh_terms: D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors*; D053858:Metabolic Networks and Pathways; D049490:Systems Biology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D051246:Glucose Transport Proteins, Facilitative