Valproate synergizes with purine nucleoside analogues to induce apoptosis of B-chronic lymphocytic leukaemia cells
Autor: | Amel Bouzar, Ruth Pettengell, Dominique Bron, Lucas Willems, Bernard Chatelain, Guy Berchem, Arsene Burny, Fenella Willis, Laurence Lagneaux, Christian Chatelain, Derek C. Macallan, Julien Defoiche, Mathieu Boxus |
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Rok vydání: | 2009 |
Předmět: |
Adult
Male medicine.drug_class Chronic lymphocytic leukemia medicine.medical_treatment Blotting Western Antineoplastic Agents Apoptosis Biology Antimetabolite Tumor Cells Cultured medicine Humans Enzyme Inhibitors Cladribine Aged Aged 80 and over Chemotherapy Microscopy Confocal Valproic Acid Histone deacetylase inhibitor Drug Synergism Hematology Middle Aged medicine.disease Leukemia Lymphocytic Chronic B-Cell Fludarabine Histone Deacetylase Inhibitors Immunology Cancer research Female lipids (amino acids peptides and proteins) Reactive Oxygen Species Nucleoside Vidarabine medicine.drug |
Zdroj: | British Journal of Haematology. 144:41-52 |
ISSN: | 1365-2141 0007-1048 |
Popis: | 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. |
Databáze: | OpenAIRE |
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