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Valproate enhances imatinib‐induced growth arrest and apoptosis in chronic myeloid leukemia cells
Author(s) -
Morotti Alessandro,
Cilloni Daniela,
Messa Francesca,
Arruga Francesca,
Defilippi Ilaria,
Carturan Sonia,
Catalano Renata,
Rosso Valentina,
Chiarenza Annalisa,
Pilatrino Chiara,
Guerrasio Angelo,
Taulli Riccardo,
Bracco Enrico,
Pautasso Marisa,
Baraban Daniela,
Gottardi Enrico,
Saglio Giuseppe
Publication year - 2006
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.21725
Subject(s) - imatinib , medicine , myeloid leukemia , cancer research , imatinib mesylate , histone deacetylase inhibitor , k562 cells , pharmacology , leukemia , abl , tyrosine kinase , immunology , histone deacetylase , biology , histone , receptor , biochemistry , gene
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 μM and valproate 5 μM for 48 hours potently enhanced imatinib‐induced growth arrest and apoptosis. In resistant cell lines and in primary MNCs derived from imatinib‐resistant 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. Cancer 2006. © 2006 American Cancer Society.