Abstract
Chronic myeloid leukemia (CML) is a malignant tumor caused by the abnormal proliferation of hematopoietic stem cells. Among a new series of acridone derivatives previously synthesized, it was found that the methoxybenzyl 5-nitroacridone derivative 8q has nanomolar cytotoxicity in vitro against human chronic myelogenous leukemia K562 cells. In order to further explore the possible anti-leukemia mechanism of action of 8q on K562 cells, a metabolomics and molecular biology study was introduced. It was thus found that most of the metabolic pathways of the G1 phase of K562 cells were affected after 8q treatment. In addition, a concentration-dependent accumulation of cells in the G1 phase was observed by cell cycle analysis. Western blot analysis showed that 8q significantly down-regulated the phosphorylation level of retinoblastoma-associated protein (Rb) in a concentration-dependent manner, upon 48 h treatment. In addition, 8q induced K562 cells apoptosis, through both mitochondria-mediated and exogenous apoptotic pathways. Taken together, these results indicate that 8q effectively triggers G1 cell cycle arrest and induces cell apoptosis in K562 cells, by inhibiting the CDK4/6-mediated phosphorylation of Rb. Furthermore, the possible binding interactions between 8q and CDK4/6 protein were clarified by homology modeling and molecular docking. In order to verify the inhibitory activity of 8q against other chronic myeloid leukemia cells, KCL-22 cells and K562 adriamycin-resistant cells (K562/ADR) were selected for the MTT assay. It is worth noting that 8q showed significant anti-proliferative activity against these cell lines after 48 h/72 h treatment. Therefore, this study provides new mechanistic information and guidance for the development of new acridones for application in the treatment of CML.
Highlights
Leukemia is a malignant clonal disease of hematopoietic stem cells that can be divided into acute and chronic types
CDK4/6 is a specific protein of the G1 phase that binds with cyclin D to form a complex, promotes phosphorylation of target retinoblastoma-associated protein (Rb), and allows the cell cycle to enter the S phase [16]
Our previous work reported that the new methoxybenzyl 5-nitroacridone 8q exhibits strong anti-proliferation activity against human chronic myelogenous leukemia K562 cells and had relatively low toxicity in vitro
Summary
Leukemia is a malignant clonal disease of hematopoietic stem cells that can be divided into acute and chronic types. At present, these hematological cancers are the 10th most common cause of death in the world [1]. Chronic myeloid leukemia (CML) is among the chronic leukemia types, and accounts for about 15–20% of all cases of leukemia in diagnosed patients [2]. The survival rate of many CML patients has been greatly improved after treatment with tyrosine kinase inhibitors such as imatinib and nilotinib. As a class of anticancer compounds, acridines and acridones have generally shown good cytotoxic or anticancer activity against acute and chronic leukemia cells [4,5,6]. Amsacrine (m-AMSA) has been used clinically in a number of countries for the treatment of acute leukemia [7,8]
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