Valproate enhances imatinib-induced growth arrest and apoptosis in CML

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Hi all. Of interest

Valproate enhances imatinib-induced growth arrest and apoptosis in

chronic myeloid leukemia cells.

Morotti A, Cilloni D, Messa F, Arruga F, Defilippi I, Carturan S,

Catalano R, Rosso V, Chiarenza A, Pilatrino C, Guerrasio A, Taulli R,

Bracco E, Pautasso M, Baraban D, Gottardi E, Saglio G

Department of Clinical and Biological Sciences, University of Turin,

Turin, Italy.

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 muM 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.

Hope this finds everyone doing well!

Barbara