Valproic acid induces apoptosis in chronic lymphocytic leukemia cells through activation of the death receptor pathway and potentiates TRAIL response.
OBJECTIVE
Chronic lymphocytic leukemia (CLL) cells develop chemoresistance over time associated with defects in apoptosis pathway. Novel treatment strategies are required to overcome resistance of cells to commonly used agents. The effects of valproic acid (VPA), an antiepileptic drug with histone deacetylase inhibitory activity, on mononuclear cells isolated from 40 CLL patients were evaluated.


METHODS
CLL cells were treated with increasing doses of VPA (0.5, 1, 2, and 5 mM). The mode of cytotoxic drug action was determined by annexin binding, DNA fragmentation, and caspase activation.


RESULTS
Exposure of CLL cells to VPA resulted in dose-dependent cytotoxicity and apoptosis in the 40 CLL patients. VPA treatment induced apoptotic changes in CLL cells including phosphatidylserine externalization and DNA fragmentation. The mean apoptotic rates were similar between IgV(H) mutated and unmutated patients, the latter presenting a more aggressive clinical course. VPA induced apoptosis via the extrinsic pathway involving engagement of the caspase-8-dependent cascade. Although CLL cells are commonly resistant to death receptor-induced apoptosis, VPA significantly increased sensitivity of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and led to downregulation of c-FLIP (L) expression. VPA caused no potentialization of TRAIL-induced apoptosis on normal B cells. In addition, VPA overcame the prosurvival effects of bone marrow stromal cells.


CONCLUSIONS
These findings point out that the combination of TRAIL and VPA, at clinically relevant concentration, may be valuable in the treatment of CLL.
Lagneaux
Laurence
L
Experimental Hematology, Bordet Institute, ULB, Brussels, Belgium. laurence.lagneaux@bordet.be
Gillet
Nicolas
N
Stamatopoulos
Basile
B
Delforge
Alain
A
Dejeneffe
Marielle
M
Massy
Martine
M
Meuleman
Nathalie
N
Kentos
Alain
A
Martiat
Philippe
P
Willems
Luc
L
Bron
Dominique
D
D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects* / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
D000927:Anticonvulsants; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D009363:Neoplasm Proteins; D010718:Phosphatidylserines; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014635:Valproic Acid; C505530:CASP8 protein, human; D053181:Caspase 8; D006655:Histone Deacetylases