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

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Valproate synergizes with purine nucleoside analogues to induce apoptosis of

B-chronic lymphocytic leukaemia cells.

Amel Baya Bouzar, Mathieu Boxus, n Defoiche, Guy Berchem, Macallan,

Ruth Pettengell, Fenella Willis, Arsene Burny, ce Lagneaux, Dominique

Bron, Bernard Chatelain, Christian Chatelain, and Luc Willems

Br J Haematol, November 1, 2008; .

National Fund for Scientific Research, Molecular and Cellular Biology, FUSAG,

Gembloux, Belgium.

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.

PMID: 19006566