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Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat

Abstract : Histone deacetylase inhibitors (HDAC) are a promising class of anticancer drugs. They can trigger the apoptotic pathway and are available for treatment of blood disorders. However, the HDACi that target HDAC class II, as vorinostat, also are potential reactivators agents of EBV, a virus that infects latently over 90% of the adult population worldwide and is associated with many type B lymphomas the study of switching between the latent cycle and the lytic cycle of EBV is essential to understand the impact of HDACi when treating B-cell lymphoma associated with EBV (salting risk virions in large quantities during the chemotherapeutic treatment).Our study focused on the effect of vorinostat (25 .mu.M for 48) on tumor B cells infected with EBV: three lines of Burkitt lymphoma (BL2B95.8, BL41B95.8 and P3HR1), three lymphoblastoid cell lines (1602 PRI and RUD) and B95.8 marmoset line in the lytic cycle of the EBV (positive control). We have demonstrated that vorinostat can induce EBV reactivation (P3HR1 and B95.8) or apoptosis (BL41B95.8, BL2B95.8, 1602, PRI and RUD) with a mutual inhibition of these two process. At the molecular level, we have shown that the active vorinostat constitutively and simultaneously initiating transcription factor reactivation MEF2D (by dephosphorylation) and MAP kinase p38 pro-apototique (phosphorylation) following the reduction in the expression of the MAP kinase phosphatase (MPK1) p38 which is a substrate. The pre-treatment with a p38 inhibitor (SB203580) showed that MAP kinase is both involved in the process of EBV reactivation and apoptosis. However, cell lines where p38 activation greatly increases during treatment with vorinostat, come directly into apoptosis, without there may EBV reactivation.Our results suggest that the level of activation of p38 MAP kinase helps regulate the balance reactivation / apoptosis of B cell EBV infected when exposed to an inducing agent for the reactivation, in particular in the case of cells B lymphoma treated with vorinostat. They raise the question of the use of HDACi in the treatment of lymphomas associated with EBV, with the risk of viral reactivation by level of intracellular activation of p38 and the need to simultaneously use an antiviral such as ganciclovir.
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Submitted on : Thursday, June 16, 2016 - 10:51:41 AM
Last modification on : Sunday, June 26, 2022 - 1:22:54 PM


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  • HAL Id : tel-01332557, version 1



Hazar Al Mohamad. Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat. Médecine humaine et pathologie. Université de Limoges, 2016. Français. ⟨NNT : 2016LIMO0014⟩. ⟨tel-01332557⟩



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