Valproate enhances imatinib-induced growth arrest and apoptosis in chronic myeloid leukemia cells.
BACKGROUND
The objective of this study was to evaluate the ability of the clinically available histone deacetylase (HDAC) inhibitor valproate to enhance the cytotoxicity of the Bcr-Abl inhibitor imatinib in imatinib-resistant cell lines.


METHODS
Interactions between imatinib, and valproate have been examined in imatinib-sensitive and -resistant chronic myeloid leukemia (CML)cell lines (K562, KCL-22, CML-T1) and in bone marrow mononuclear cells (MNCs) derived from imatinib-resistant CML patients.


RESULTS
In imatinib-sensitive cell lines, cotreatment with imatinib 0.5 muM and valproate 5 microM for 48 hours potently enhanced imatinib-induced growth arrest and apoptosis. In resistant cell lines and in primary MNCs derived from imatinib-rsistant patients, valproate restored sensitivity to the cytotoxic effects of imatinib. Coexposure of cells to valproate and imatinib was associated with repression of several genes involved in Bcr-Abl transformation. In particular, the combination valproate-imatinib downregulated the expression of Bcr-Abl and the antiapoptotic protein Bcl-2, which is particularly overexpressed in imatinib-resistant clones.


CONCLUSIONS
Data from this study suggested that administration of the clinically available HDAC inhibitor valproate may be a powerful strategy to enhance cytotoxic effects of imatinib in those patient resistant to imatinib or in which complete cytogenetic remission has been not reached.
Morotti
Alessandro
A
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. alessandromorotti@yahoo.it
Cilloni
Daniela
D
Messa
Francesca
F
Arruga
Francesca
F
Defilippi
Ilaria
I
Carturan
Sonia
S
Catalano
Renata
R
Rosso
Valentina
V
Chiarenza
Annalisa
A
Pilatrino
Chiara
C
Guerrasio
Angelo
A
Taulli
Riccardo
R
Bracco
Enrico
E
Pautasso
Marisa
M
Baraban
Daniela
D
Gottardi
Enrico
E
Saglio
Giuseppe
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D014635:Valproic Acid; D000068877:Imatinib Mesylate