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Dexamethasone induces a heat‐stress response that ameliorates the conformational consequences on antithrombin of l ‐asparaginase treatment
Author(s) -
HERNÁNDEZESPINOSA D.,
MIÑANO A.,
ORDÓÑEZ A.,
MOTA R.,
MARTÍNEZMARTÍNEZ I.,
VICENTE V.,
CORRAL J.
Publication year - 2009
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2009.03449.x
Subject(s) - antithrombin , serpin , intracellular , dexamethasone , endoplasmic reticulum , unfolded protein response , prednisone , heat shock protein , medicine , pharmacology , asparaginase , endocrinology , chemistry , immunology , heparin , biochemistry , leukemia , lymphoblastic leukemia , gene
Summary. 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.