Valproate enhances imatinib‐induced growth arrest and apoptosis in chronic myeloid leukemia cells

Abstract

BACKGROUNDThe 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.METHODSInteractions 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.RESULTSIn 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.CONCLUSIONSData 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.

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

“…The upregulation of p21 by VPA was observed earlier in myeloid leukemia 28 and multiple myeloma. 46 Similar results have been observed for cyclin D1 and cyclin E in acute leukemia.…”

“…26 VPA association with monoclonal antibodies is furthermore described in in vitro studies. 27,28 Finally, VPA is well tolerated, and its effective concentration can be easily achieved in humans. All of these observations indicate that VPA could be a promising anticancer drug and strongly suggest the use of this epigenetic therapy in CLL treatment.…”

NF‐kB inhibition as a strategy to enhance etoposide‐induced apoptosis in K562 cell line

“…Data shown are the media of at least three independent experiments. Annexin V positive cells have been measured as described elsewhere [18].…”

Effects of the histone deacetylase inhibitor valproic acid on the sensitivity of anaplastic thyroid cancer cell lines to imatinib

“…These drugs induce differentiation, growth arrest and apoptosis of transformed cells (16)(17)(18). Several HDIs such as SAHA (19), LAQ824 (20), MS-275 (21) and valproic acid (22) enhance imatinib-induced growth arrest and apoptosis in imatinib-sensitive and -resistant leukaemic cell lines.…”