Acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells: application of metabolomics in mechanistic studies of antitumor agents

• Published in: PloS one 2013-05, Vol.8 (5), p.e63572-e63572
• Main Authors: Wang, Yini, Gao, Dan, Chen, Zhe, Li, Shangfu, Gao, Chunmei, Cao, Deliang, Liu, Feng, Liu, Hongxia, Jiang, Yuyang
• Format: Article
• Language: English
• Subjects: Acridines - chemistry; Acridines - pharmacology; Acridones - chemistry; Acridones - pharmacology; Anticancer properties; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor agents; Apoptosis; Apoptosis - drug effects; Bioindicators; Biology; Biomarkers; Biomarkers - metabolism; Cancer; Cancer research; Caspase; Caspase-3; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chromatography; Chromatography, Liquid; Cytochrome; Cytochrome c; Data acquisition; Data processing; Deoxyribonucleic acid; Discriminant Analysis; DNA; Drugs; Gene expression; Glutathione; Glycine; Humans; Laboratories; Least-Squares Analysis; Leukemia; Leukemia - metabolism; Leukemia - pathology; Lipid peroxidation; Lipids; Malondialdehyde; Malondialdehyde - metabolism; Mass Spectrometry; Medicine; Membrane potential; Metabolic pathways; Metabolism; Metabolites; Metabolomics; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Models, Biological; Molecular biology; NMR; Nuclear magnetic resonance; Oxidative stress; Oxidative Stress - drug effects; Oxygen; Peroxidation; Principal Component Analysis; Principal components analysis; Reactive oxygen species; Reactive Oxygen Species - metabolism; Scientific imaging; Urine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063572

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.