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

Amel Baya Bouzar, Mathieu Boxus, Julien Defoiche, Guy Berchem, Derek Macallan, Ruth Pettengell, Fenella Willis, Arsène Burny, Laurence Lagneaux, Dominique Bron, Bernard Chatelain, Christian Chatelain, Luc Willems*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

48 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)41-52
Number of pages12
JournalBritish Journal of Haematology
Volume144
Issue number1
DOIs
Publication statusPublished - Jan 2009
Externally publishedYes

Keywords

  • Apoptosis
  • Chronic lymphocytic leukaemia
  • Cladribine
  • Fludarabine
  • Valproate

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