Abstract
Expression of oncogenic Bcr-Abl inhibits cell differentiation of hematopoietic stem/progenitor cells in chronic myeloid leukemia (CML). Differentiation therapy is considered to be a new strategy for treating this type of leukemia. Aclacinomycin A (ACM) is an antitumor antibiotic. Previous studies have shown that ACM induced erythroid differentiation of CML cells. In this study, we investigate the effect of ACM on the sensitivity of human CML cell line K562 to Bcr-Abl specific inhibitor imatinib (STI571, Gleevec). We first determined the optimal concentration of ACM for erythroid differentiation but not growth inhibition and apoptosis in K562 cells. Then, pretreatment with this optimal concentration of ACM followed by a minimally toxic concentration of imatinib strongly induced growth inhibition and apoptosis compared to that with simultaneous co-treatment, indicating that ACM-induced erythroid differentiation sensitizes K562 cells to imatinib. Sequential treatment with ACM and imatinib induced Bcr-Abl down-regulation, cytochrome c release into the cytosol, and caspase-3 activation, as well as decreased Mcl-1 and Bcl-xL expressions, but did not affect Fas ligand/Fas death receptor and procaspase-8 expressions. ACM/imatinib sequential treatment-induced apoptosis was suppressed by a caspase-9 inhibitor and a caspase-3 inhibitor, indicating that the caspase cascade is involved in this apoptosis. Furthermore, we demonstrated that ACM induced erythroid differentiation through the p38 mitogen-activated protein kinase (MAPK) pathway. The inhibition of erythroid differentiation by p38MAPK inhibitor SB202190, p38MAPK dominant negative mutant or p38MAPK shRNA knockdown, reduced the ACM/imatinib sequential treatment-mediated growth inhibition and apoptosis. These results suggest that differentiated K562 cells induced by ACM-mediated p38MAPK pathway become more sensitive to imatinib and result in down-regulations of Bcr-Abl and anti-apoptotic proteins, growth inhibition and apoptosis. These results provided a potential management by which ACM might have a crucial impact on increasing sensitivity of CML cells to imatinib in the differentiation therapeutic approaches.
Highlights
Chronic myeloid leukemia (CML) is a malignant hematological disease of hematopoietic stem/progenitor cells characterized by the presence of Bcr-Abl oncoprotein, a constitutively active tyrosine kinase produced as a reciprocal translocation between chromosome 9 and 22 [1]
In order to investigate whether ACM-induced differentiation can increase sensitivity of K562 cells to imatinib, we first determined the concentration of ACM required for erythroid differentiation but not growth inhibition and apoptosis
The inability to treat successfully the disease is probably due to the survival of quiescent CML stem cells
Summary
Chronic myeloid leukemia (CML) is a malignant hematological disease of hematopoietic stem/progenitor cells characterized by the presence of Bcr-Abl oncoprotein, a constitutively active tyrosine kinase produced as a reciprocal translocation between chromosome 9 and 22 [1]. CML progresses from the chronic phase to the blast crisis phase, in which differentiation becomes arrested. This results in the accumulation of undifferentiated CML progenitors in bone marrow and peripheral blood [3,4]. A specific inhibitor of Bcr-Abl tyrosine kinase, imatinib (STI571 or Gleevec), is highly effective in treating CML patients, and is used as first-line treatment for CML [3,4]. Differentiation therapy is regarded as a promising therapeutic approach
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