Abstract
Dasatinib is a compound developed for chronic myeloid leukemia as a multi-targeted kinase inhibitor against wild-type BCR-ABL and SRC family kinases. Valproic acid (VPA) is an anti-epileptic drug that also acts as a class I histone deacetylase inhibitor. The aim of this research was to determine the anti-leukemic effects of dasatinib and VPA in combination and to identify their mechanism of action in acute myeloid leukemia (AML) cells. Dasatinib was found to exert potent synergistic inhibitory effects on VPA-treated AML cells in association with G1 phase cell cycle arrest and apoptosis induction involving the cleavage of poly (ADP-ribose) polymerase and caspase-3, -7 and -9. Dasatinib/VPA-induced cell death thus occurred via caspase-dependent apoptosis. Moreover, MEK/ERK and p38 MAPK inhibitors efficiently inhibited dasatinib/VPA-induced apoptosis. The combined effect of dasatinib and VPA on the differentiation capacity of AML cells was more powerful than the effect of each drug alone, being sufficiently strong to promote AML cell death through G1 cell cycle arrest and caspase-dependent apoptosis. MEK/ERK and p38 MAPK were found to control dasatinib/VPA-induced apoptosis as upstream regulators, and co-treatment with dasatinib and VPA to contribute to AML cell death through the regulation of differentiation capacity. Taken together, these results indicate that combined dasatinib and VPA treatment has a potential role in anti-leukemic therapy.
Highlights
Acute myeloid leukemia (AML) remains one of the most difficult hematologic malignancies to treat [1]
Combined dasatinib and Valproic acid (VPA) treatment led to a marked decrease on CD11b expression in HL60 cells, and the change occurred in a time-dependent manner (Figs. 1A and B)
We further investigated the effects of dasatinib and VPA on the Peripheral blood mononuclear cells (PBMC) and bone marrow cells (BMC) obtained from the two acute myeloid leukemia (AML) patients
Summary
Acute myeloid leukemia (AML) remains one of the most difficult hematologic malignancies to treat [1]. Dasatinib (BMS-354825) is an FDA-approved small molecular compound that was developed primarily to treat chronic myeloid leukemia (CML) as a multi-targeted tyrosine kinase inhibitor against wild-type BCR-ABL and SRC family kinases [2]. The off-target effects of tyrosine kinase inhibitors, including dasatinib, on AML differentiation have attracted considerable research interest in the past few years. Imatinib, the first BCR/ABL inhibitor, was discovered to exert an effect on the potentiation of all-transretinoic acid (ATRA)-induced AML differentiation [6], and the epidermal growth factor receptor inhibitor gefitinib was later confirmed to enhance the ATRA-induced differentiation of AML cells [7,8]. Dasatinib demonstrated similar effects on such differentiation in a separate study [2]
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