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.
Centro Regional de Hemodonación, University of Murcia, Murcia, Spain.
D
D
Hernández-Espinosa
A
A
Miñano
A
A
Ordóñez
R
R
Mota
I
I
Martínez-Martínez
V
V
Vicente
J
J
Corral
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