Abstract
A new acridone derivative, 2-aminoacetamido-10-(3, 5-dimethoxy)-benzyl-9(10H)-acridone hydrochloride (named 8a) synthesized in our lab shows potent antitumor activity, but the mechanism of action remains unclear. Herein, we report the use of an UPLC/Q-TOF MS metabolomic approach to study the effects of three compounds with structures optimized step-by-step, 9(10H)-acridone (A), 10-(3,5-dimethoxy)benzyl-9(10H)-acridone (I), and 8a, on CCRF-CEM leukemia cells and to shed new light on the probable antitumor mechanism of 8a. Acquired data were processed by principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) to identify potential biomarkers. Comparing 8a-treated CCRF-CEM leukemia cells with vehicle control (DMSO), 23 distinct metabolites involved in five metabolic pathways were identified. Metabolites from glutathione (GSH) and glycerophospholipid metabolism were investigated in detail, and results showed that GSH level and the reduced/oxidized glutathione (GSH/GSSG) ratio were significantly decreased in 8a-treated cells, while L-cysteinyl-glycine (L-Cys-Gly) and glutamate were greatly increased. In glycerophospholipid metabolism, cell membrane components phosphatidylcholines (PCs) were decreased in 8a-treated cells, while the oxidative products lysophosphatidylcholines (LPCs) were significantly increased. We further found that in 8a-treated cells, the reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) were notably increased, accompanied with decrease of mitochondrial transmembrane potential, release of cytochrome C and activation of caspase-3. Taken together our results suggest that the acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells. The UPLC/Q-TOF MS based metabolomic approach provides novel insights into the mechanistic studies of antitumor drugs from a point distinct from traditional biological investigations.
Highlights
Acridone derivatives with a unique molecular structure of two benzene rings fused together possess a wide range of biological activities, such as antivirus [1], anti-allergy [2], anti-malaria [3] and antitumor [4,5,6]
Results revealed that 8a possessed the strongest anti-proliferative activity and the most significant discrimination in the cell metabolic phenotypes compared with vehicle control group
Comparing 8a with the control group, twenty three distinct metabolites involved in five metabolic pathways were identified
Summary
Acridone derivatives with a unique molecular structure of two benzene rings fused together possess a wide range of biological activities, such as antivirus [1], anti-allergy [2], anti-malaria [3] and antitumor [4,5,6]. This feature is attributed to the semiplanar heterocyclic structure which appreciably interacts with different biomolecular targets. The antitumor activity of acridone derivatives has attracted an increasing interest, and a large number of acridone derivatives have been chemically synthesized and tested for antitumor activity. The understanding of intensive antitumor mechanisms is limited because of the limitations of these conventional molecular biology approaches, such as poor repeatability, less quantity of data, and time-consuming and laboursome
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