| Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment. | |
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MedLine Citation:
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PMID: 19422445 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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D Hernández-Espinosa; A Miñano; A Ordóñez; R Mota; I Martínez-Martínez; V Vicente; J Corral |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-04-27 |
Journal Detail:
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Title: Journal of thrombosis and haemostasis : JTH Volume: 7 ISSN: 1538-7836 ISO Abbreviation: J. Thromb. Haemost. Publication Date: 2009 Jul |
Date Detail:
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Created Date: 2009-07-06 Completed Date: 2009-10-22 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101170508 Medline TA: J Thromb Haemost Country: England |
Other Details:
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Languages: eng Pagination: 1128-33 Citation Subset: IM |
Affiliation:
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Centro Regional de Hemodonación, University of Murcia, Murcia, Spain. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adolescent Adult Antithrombins / chemistry* Asparaginase / therapeutic use* Base Sequence Child Child, Preschool DNA Primers Dexamethasone / pharmacology* Female Heat-Shock Response / drug effects* Humans Male Middle Aged Polymerase Chain Reaction Protein Conformation Young Adult |
| Chemical | |
Reg. No./Substance:
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0/Antithrombins; 0/DNA Primers; 50-02-2/Dexamethasone; EC 3.5.1.1/Asparaginase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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