Linked Life Data

21166896

Source:http://linkedlifedata.com/resource/pubmed/id/21166896

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
1
pubmed:dateCreated
2010-12-20
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
1365-2958
pubmed:author
pubmed:copyrightInfo
© 2010 Blackwell Publishing Ltd.
pubmed:issnType
Electronic
pubmed:volume
79
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
94-108
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
A domino effect in drug action: from metabolic assault towards parasite differentiation.
pubmed:affiliation
Department of Molecular Cell Physiology, Faculty of Earth and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1085, NL-1081 HV Amsterdam, the Netherlands.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't