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

Wang Y, Gao D, Chen Z, Li S, Gao C, Cao D, Liu F, Liu H, Jiang Y - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Tsinghua University, Beijing, China.

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.

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The hypothetic scheme of the action mechanism of 8a. Mito, mitochondrial.
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pone-0063572-g006: The hypothetic scheme of the action mechanism of 8a. Mito, mitochondrial.

Mentions: In this study, an UPLC/Q-TOF MS based metabolomic method was established to investigate the metabolite changes of two acridone derivatives (I and 8a) and their parental compound A in CCRF-CEM cells in order to predict hypothetic antitumor mechanism of 8a in CCRF-CEM cells. 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. Two metabolic pathways, i.e., glutathione and glycerophospholipid metabolism were investigated in depth to understand the cell death mechanism induced by 8a; 11 metabolites were identified as biomarkers for antitumor activity. Biological studies were further conducted to confirm the underlying cellular events. Combining the metabolomic and biological results, we propose a schematic hypothesis for the anti-proliferative mechanism of 8a (Figure 6). In CCRF-CEM cells, 8a provokes oxidative stress, which in turn leads to lipid peroxidation and mitochondrial lesions and potential changes. Cytochrome C release resulting from mitochondrial potential changes then triggers caspase-3 mediated apoptosis. These findings enhance our understanding of the action mechanisms of 8a anti-proliferation and aid in their incorporation into further improvement.


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

Wang Y, Gao D, Chen Z, Li S, Gao C, Cao D, Liu F, Liu H, Jiang Y - PLoS ONE (2013)

The hypothetic scheme of the action mechanism of 8a. Mito, mitochondrial.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3646819&req=5

pone-0063572-g006: The hypothetic scheme of the action mechanism of 8a. Mito, mitochondrial.
Mentions: In this study, an UPLC/Q-TOF MS based metabolomic method was established to investigate the metabolite changes of two acridone derivatives (I and 8a) and their parental compound A in CCRF-CEM cells in order to predict hypothetic antitumor mechanism of 8a in CCRF-CEM cells. 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. Two metabolic pathways, i.e., glutathione and glycerophospholipid metabolism were investigated in depth to understand the cell death mechanism induced by 8a; 11 metabolites were identified as biomarkers for antitumor activity. Biological studies were further conducted to confirm the underlying cellular events. Combining the metabolomic and biological results, we propose a schematic hypothesis for the anti-proliferative mechanism of 8a (Figure 6). In CCRF-CEM cells, 8a provokes oxidative stress, which in turn leads to lipid peroxidation and mitochondrial lesions and potential changes. Cytochrome C release resulting from mitochondrial potential changes then triggers caspase-3 mediated apoptosis. These findings enhance our understanding of the action mechanisms of 8a anti-proliferation and aid in their incorporation into further improvement.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Tsinghua University, Beijing, China.

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.

Show MeSH
Related in: MedlinePlus