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Cell Death Dis ; 4: e738, 2013 Jul 25.
Article in English | MEDLINE | ID: mdl-23887629

ABSTRACT

Abexinostat is a pan histone deacetylase inhibitor (HDACi) that demonstrates efficacy in malignancy treatment. Like other HDACi, this drug induces a profound thrombocytopenia whose mechanism is only partially understood. We have analyzed its effect at doses reached in patient plasma on in vitro megakaryopoiesis derived from human CD34(+) cells. When added at day 0 in culture, abexinostat inhibited CFU-MK growth, megakaryocyte (MK) proliferation and differentiation. These effects required only a short incubation period. Decreased proliferation was due to induction of apoptosis and was not related to a defect in TPO/MPL/JAK2/STAT signaling. When added later (day 8), the compound induced a dose-dependent decrease (up to 10-fold) in proplatelet (PPT) formation. Gene profiling from MK revealed a silencing in the expression of DNA repair genes with a marked RAD51 decrease at protein level. DNA double-strand breaks were increased as attested by elevated γH2AX phosphorylation level. Moreover, ATM was phosphorylated leading to p53 stabilization and increased BAX and p21 expression. The use of a p53 shRNA rescued apoptosis, and only partially the defect in PPT formation. These results suggest that HDACi induces a thrombocytopenia by a p53-dependent mechanism along MK differentiation and a p53-dependent and -independent mechanism for PPT formation.


Subject(s)
Benzofurans/adverse effects , Histone Deacetylase Inhibitors/adverse effects , Hydroxamic Acids/adverse effects , Thrombocytopenia/chemically induced , Thrombocytopenia/metabolism , Tumor Suppressor Protein p53/metabolism , Acetylation , Benzofurans/administration & dosage , Cell Growth Processes/physiology , DNA Repair , Histone Deacetylase Inhibitors/administration & dosage , Humans , Hydroxamic Acids/administration & dosage , Phosphorylation , Signal Transduction , Thrombocytopenia/genetics , Tumor Suppressor Protein p53/genetics
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