Valproate synergizes with purine nucleoside analogues to induce apoptosis of B-chronic lymphocytic leukaemia cells.
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.
Bouzar
Amel Baya
AB
National Fund for Scientific Research, Molecular and Cellular Biology, FUSAG, Gembloux, Belgium.
Boxus
Mathieu
M
Defoiche
Julien
J
Berchem
Guy
G
Macallan
Derek
D
Pettengell
Ruth
R
Willis
Fenella
F
Burny
Arsène
A
Lagneaux
Laurence
L
Bron
Dominique
D
Chatelain
Bernard
B
Chatelain
Christian
C
Willems
Luc
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D017338:Cladribine / Q000627:therapeutic use; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000627:therapeutic use*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D017382:Reactive Oxygen Species; D017338:Cladribine; D014635:Valproic Acid; D014740:Vidarabine; C024352:fludarabine