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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Ali, A. Bluteau, O. Messaoudi, K. Palazzo, A. Boukour, S. Lordier, L. Lecluse, Y. Rameau, P. Kraus-Berthier, L. Jacquet-Bescond, A. Lelièvre, H. Depil, S. Dessen, P. Solary, E. Raslova, H. Vainchenker, W. Plo, I. Debili, N. |
| Description | Country affiliation: France Author Affiliation: Ali A ( Institut National de la Santé et de la Recherche Médicale, UMR 1009, Equipe labellisée Ligue Contre le Cancer, Laboratoire d'Excellence GR-Ex.114 rue Edouard Vaillant, 94805 Villejuif, France.) |
| 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. |
| File Format | HTM / HTML |
| e-ISSN | 20414889 |
| DOI | 10.1038/cddis.2013.260 |
| Journal | Cell Death and Disease |
| Volume Number | 4 |
| Language | English |
| Publisher | Nature Publishing Group |
| Publisher Date | 2013-07-25 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Thrombocytopenia Research Support, Non-u.s. Gov't Dna Repair Phosphorylation Adverse Effects Signal Transduction Administration & Dosage Metabolism Benzofurans Hydroxamic Acids Chemically Induced Cell Growth Processes Discipline Cell Biology Tumor Suppressor Protein P53 Genetics Histone Deacetylase Inhibitors Physiology Acetylation |
| Content Type | Text |
| Resource Type | Article |
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