Abstract
BackgroundAcute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study.MethodsSynergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed.ResultsThe combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G0/G1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G0/G1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells.ConclusionsTherefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy
Radotinib enhances Ara-C-induced AML cell death in AML cell lines and primary patient samples HL60 cells were treated with various concentrations of radotinib (0, 10, 30, 40 and 50 μM) and Ara-C (0, 40, 80, 120 and 160 nM) for 48 h
Radotinib and Ara-C significantly inhibited the viability of the HL60 cells in a dosedependent manner (Supplementary Figure 1A and 1B)
Summary
Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. There is a need for the development of novel chemotherapeutic agents that could treat AML effectively. We investigated combination effects of radotinib and Ara-C on AML in this study. Acute myeloid leukemia (AML) is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and/or peripheral blood [1, 2]. It is a heterogeneous disease, characterized by numerous cytogenetic and molecular alterations [3]. The development of novel chemotherapeutic agents that can treat AML effectively is required
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