Document Detail

Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment.
MedLine Citation:
PMID:  19422445     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: L-asparaginase (L-ASP) treatment of patients with acute lymphoblastic leukemia causes a severe antithrombin deficiency by intracellular retention of this serpin within the endoplasmic reticulum (ER) of hepatic cells, and a subsequent risk of thrombosis. Interestingly, co-administration of dexamethasone with L-ASP seems to reduce the risk of thrombosis. OBJECTIVES: We have investigated the effect of two corticoids, dexamethasone and prednisone, on the conformational consequences of L-ASP treatment on antithrombin. PATIENTS/METHODS: Levels, activity, conformation and immunohistological features of antithrombin were studied in patients, cell and mice models. Because of the importance of the steroid receptor-heat stress response (HSR) axis, and the role of unfolded protein response (UPR) in conformational diseases, we also evaluated Hsp27, Hsp70, Hsp90, HSF-1 and ER chaperons (Grp78 and Grp94). RESULTS: In all models, L-ASP alone or in combination with prednisone caused the intracellular retention of antithrombin associated with a severe deficiency. In contrast, the combination of L-ASP with dexamethasone ameliorated both the deficiency and intracellular retention of the serpin, which is associated with increased expression of heat shock proteins and ER-chaperons. CONCLUSIONS: These results suggest a protective effect of dexamethasone on the conformational consequences of L-ASP on antithrombin as a result of exacerbated HSR and UPR that help to explain the reduced risk of thrombosis reported in patients that follow this scheme of treatment.
D Hernández-Espinosa; A Miñano; A Ordóñez; R Mota; I Martínez-Martínez; V Vicente; J Corral
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-04-27
Journal Detail:
Title:  Journal of thrombosis and haemostasis : JTH     Volume:  7     ISSN:  1538-7836     ISO Abbreviation:  J. Thromb. Haemost.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-07-06     Completed Date:  2009-10-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101170508     Medline TA:  J Thromb Haemost     Country:  England    
Other Details:
Languages:  eng     Pagination:  1128-33     Citation Subset:  IM    
Centro Regional de Hemodonación, University of Murcia, Murcia, Spain.
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MeSH Terms
Antithrombins / chemistry*
Asparaginase / therapeutic use*
Base Sequence
Child, Preschool
DNA Primers
Dexamethasone / pharmacology*
Heat-Shock Response / drug effects*
Middle Aged
Polymerase Chain Reaction
Protein Conformation
Young Adult
Reg. No./Substance:
0/Antithrombins; 0/DNA Primers; 50-02-2/Dexamethasone; EC

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