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Valproate synergizes with purine nucleoside analogues to induce apoptosis of B-chronic lymphocytic leukaemia cells.

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Bouzar, Amel Baya Boxus, Mathieu Defoiche, Julien Berchem, Guy Macallan, Derek Willems, Luc

Resistance to chemotherapy and drug toxicity are two major concerns of chronic lymphocytic leukaemia (B-CLL) treatment by purine nucleoside analogues (PNA, i.e. fludarabine and cladribine). We hypothesized that targeting epigenetic changes might address these issues and evaluated the effect of the histone deacetylase inhibitor valproate (VPA) at a clinically relevant concentration. VPA acted in a highly synergistic/additive manner with fludarabine and cladribine to induce apoptosis of B-CLL cells. Importantly, VPA also restored sensitivity to fludarabine in B cells from poor prognosis CLL patients who became resistant to chemotherapy. Mechanism of apoptosis induced by VPA alone or combined with fludarabine or to cladribine was caspase-dependent and involved the extrinsic pathway. VPA, but neither fludarabine nor cladribine, enhanced the production of reactive oxygen species (ROS) and inhibition of ROS with N-acetylcysteine decreases apoptosis of CLL cells. VPA stimulates hyperphosphorylation of p42/p44 ERK, cytochrome c release and overexpression of Bax and Fas. Together, our data indicate that VPA may ameliorate the outcome of PNA-based therapeutic protocols and provide a potential alternative treatment in both the relapsed and front-line resistant patients and in patients with high risk features.

Document type Article de périodique (Journal article)
Access type Accès restreint
Publication date 2009
Language Anglais
Journal information "British Journal of Haematology" - Vol. 144, no.1, p. 41-52 (2009)
Peer reviewed yes
Publisher Wiley-Blackwell Publishing Ltd. ((United Kingdom) Oxford)
issn 0007-1048
e-issn 1365-2141
Publication status Publié
Affiliations UCL - (MGD) Laboratoire de biologie clinique
UCL - (MGD) Service d'hématologie
MESH Subject Adult ; Female ; Histone Deacetylase Inhibitors ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; Male ; Microscopy, Confocal ; Middle Aged ; Reactive Oxygen Species ; Tumor Cells, Cultured ; Valproic Acid ; Aged ; Vidarabine ; Aged, 80 and over ; Antineoplastic Agents ; Apoptosis ; Blotting, Western ; Cladribine ; Drug Synergism ; Enzyme Inhibitors
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Bibliographic reference Bouzar, Amel Baya ; Boxus, Mathieu ; Defoiche, Julien ; Berchem, Guy ; Macallan, Derek ; et. al. Valproate synergizes with purine nucleoside analogues to induce apoptosis of B-chronic lymphocytic leukaemia cells.. In: British Journal of Haematology, Vol. 144, no.1, p. 41-52 (2009)
Permanent URL http://hdl.handle.net/2078.1/123903