Dexamethasone induces a heat-stress response that ameliorates the conformational consequences on antithrombin of L-asparaginase treatment.
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.


OBJECTIVE
We have investigated the effect of two corticoids, dexamethasone and prednisone, on the conformational consequences of L-ASP treatment on antithrombin.


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.
Hernández-Espinosa
D
D
Centro Regional de Hemodonación, University of Murcia, Murcia, Spain.
Miñano
A
A
Ordóñez
A
A
Mota
R
R
Martínez-Martínez
I
I
Vicente
V
V
Corral
J
J
D000293:Adolescent; D000328:Adult; D000991:Antithrombins / Q000737:chemistry*; D001215:Asparaginase / Q000627:therapeutic use*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D003907:Dexamethasone / Q000494:pharmacology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D018869:Heat-Shock Response / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D055815:Young Adult
D000991:Antithrombins; D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D003907:Dexamethasone; D001215:Asparaginase