The Experts below are selected from a list of 96 Experts worldwide ranked by ideXlab platform
Yuyang Jiang - One of the best experts on this subject based on the ideXlab platform.
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combing metabolomics with bioanalysis methods to study the antitumor mechanism of the new Acridone Derivative 8q on ccrf cem cells 8q induced mitochondrial mediated apoptosis and targeted the pi3k akt foxo1 pathway
Journal of Pharmaceutical and Biomedical Analysis, 2018Co-Authors: Ning Wang, Dan Gao, Feng Liu, Hongxia Liu, Bin Zhang, Feng Jin, Yuyang JiangAbstract:Abstract A novel Acridone Derivative, N-(2-(dimethylamino)ethyl)-1-((3-methoxybenzyl)amino)-5- nitro-9-oxo-9,10-dihydro-acridine-4-carboxamide (8q), which was synthesized in our lab, showed potent anti-leukaemia activity against CCRF-CEM cells. Moreover, in silico predictions showed that 8q conformed to the rule of five and displayed low toxicity. However, the mechanism of anti-leukaemia action remains unclear. The aim of this research was to reveal the probable anti-leukaemia mechanism of 8q on CCRF-CEM cells. Flow cytometry assay demonstrated that 8q induced apoptosis. The expression of caspase family proteins results showed that 8q could only promote cleaved caspase-3, 7 and 9 expressions without affecting cleaved caspase-8 protein, hinting that 8q induced mitochondrial-mediated apoptosis. Further, we detected 3 indicators of mitochondrial lesions, including increased of Cyt-C release, with a decrease in MMP and ATP levels. Next, metabolomics were introduced to assist in the research of the anti-leukaemia mechanism of 8q. The metabolomics results showed that 100 nM 8q could increase the level of GSH, and decrease its oxidation products. These indicated 8q could influence the ROS, which derived by mitochondria. Then we examined the effect of 8q on intracellular ROS levels. What is particularly interesting is that 8q inhibited cell ROS stress at low concentration and stimulated ROS stress at high concentration. The pro-apoptosis mechanisms of 8q were then explored. 8q significantly decreased anti-apoptotic proteins Bcl-2 and Bcl-xL expression, whereas it up-regulated the pro-apoptotic proteins Bax, Bak, Bad, Bik and Puma expression. In addition, 8q dramatically inhibited the expression of FASN, which is related to fatty acid metabolism. Furthermore, PI3K, AKT and FOXO1 were inactivated, and the expression of total AKT was also inhibited by 8q treatment, which promoted intrinsic apoptosis. In conclusion, these findings demonstrate that 8q can induce mitochondrial lesions and promote mitochondrial-mediated pathway apoptosis by regulating the expression of Bcl-2 family proteins and inhibiting the activity of the PI3K/AKT/FOXO1 signaling pathway.
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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. PLoS One 2013
2016Co-Authors: Yini Wang, Dan Gao, Zhe Chen, Chunmei Gao, Deliang Cao, Feng Liu, Hongxia Liu, Yuyang JiangAbstract: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 togethe
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exposure of ccrf cem cells to Acridone Derivative 8a triggers tumor death via multiple mechanisms
Proteomics, 2016Co-Authors: Yini Wang, Dan Gao, Chunmei Gao, Deliang Cao, Hongxia Liu, Bizhu Chu, Yuyang JiangAbstract:A newly synthesized Acridone Derivative 8a shows potent antitumor activity against CCRF-CEM leukemia cells. Herein, the first proteomic study of 8a effects in CCRF-CEM cells was performed by 2D nano-LC-ESI-MS/MS to better understand the mechanisms of action of 8a. Data analyses based on PLGS, STRING, Cytoscape, and database for annotation, visualization, and integrated discovery identified 55 proteins that were differentially expressed in response to 8a exposure. Multiple cellular pathways were affected, including chromatin organization, energy metabolism, DNA repair, oxidative-stress, and apoptosis. The changes in protein expression were further verified for PKM2. Moreover, 8a lowered down the expression of HEX and PFK-1. Lactate production was decreased in 8a-treated cells, indicating suppression of glycolysis. The elevated XRCC6 and decreased histone expression levels suggested increased DNA damage in 8a-treated cells, which was confirmed by the increased γ-H2AX foci. Molecular docking of 8a with DNA demonstrated direct interactions of 8a with DNA through three hydrogen bonds and four π-π interactions, potentially explaining the mode of action that 8a damaged to DNA. The differential protein profiling and dysfunction of metabolic pathways induced by 8a provide novel insights into the potential action mechanisms of 8a.
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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
PLOS ONE, 2013Co-Authors: Yini Wang, Dan Gao, Zhe Chen, Chunmei Gao, Deliang Cao, Feng Liu, Hongxia Liu, Yuyang JiangAbstract: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.
Yini Wang - One of the best experts on this subject based on the ideXlab platform.
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comparative proteomic analysis of histone modifications upon Acridone Derivative 8a induced ccrf cem cells by data independent acquisition
Journal of Proteome Research, 2020Co-Authors: Yini Wang, Dan Gao, Bowen Zhong, Dongdong Zhan, Mingwei Liu, Yi Wang, Jun QinAbstract:The lead compound Acridone Derivative 8a showed potent antiproliferative activity by inducing DNA damage through direct stacking with DNA bases and triggering ROS in CCRF-CEM cells. To define the chromatin alterations during DNA damage sensing and repair, a detailed quantitative map of single and coexisting histone post-translational modifications (PTMs) in CCRF-CEM cells affected by 8a was performed by the Data Independent Acquisition (DIA) method on QE-plus. A total of 79 distinct and 164 coexisting histone PTMs were quantified, of which 16 distinct histone PTMs were significantly altered when comparing 8a-treated cells with vehicle control cells. The changes in histone PTMs were confirmed by Western blotting analysis for three H3 and one H4 histone markers. The up-regulated dimethylation on H3K9, H3K36, and H4K20 implied that CCRF-CEM cells might accelerate DNA damage repair to counteract the DNA lesion induced by 8a, which was verified by an increment in the 53BP1 foci localization at the damaged DNA. Most of the significantly altered PTMs were involved in transcriptional regulation, including down-regulated acetylation on H3K18, H3K27, and H3K122, and up-regulated di- and trimethylation on H3K9 and H3K27. This transcription-silencing phenomenon was associated with G2/M cell cycle arrest after 8a treatment by flow cytometry. This study shows that the DIA proteomics strategy provides a sensitive and accurate way to characterize the coexisting histone PTMs changes and their cross-talk in CCRF-CEM cells after 8a treatment. Specifically, histone PTMs rearrange transcription-silencing, and cell cycle arrest DNA damage repair may contribute to the mechanism of epigenetic response affected by 8a.
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changes in cellular glycosylation of leukemia cells upon treatment with Acridone Derivatives yield insight into drug action
Proteomics, 2016Co-Authors: Yini Wang, Dan Gao, Hongxia Liu, Dayoung Park, Ace G Galermo, Carlito B LebrillaAbstract:A new Acridone Derivative 2-aminoacetamido-10-(3, 5-dimethoxy)-benzyl-9(10H)-Acridone hydrochloride (8a) has been shown to have potent antitumor activity. In order to understand the underlying action mechanism of 8a, three compounds of the same class with structures optimized step-by-step, 9(10H)-Acridone (A), 10-(3,5-dimethoxy) benzyl-9(10H)-Acridone (I) and 8a, were exposed to CCRF-CEM leukemia cell to determine the N-glycosylation changes using the microfluidic HPLC-chip-TOF MS platform. N-Glycans from whole cell lysates (WCL) and cell membranes (CM) were analyzed using isomer-sensitive chip-based porous graphitized carbon nano-LC/MS. A total of 223 N-glycan compositions and 398 N-glycan compounds were identified. Comparison of the two analyses showed that more apparent changes were observed in the CM compared with WCL, suggesting that CM may be a more sensitive indicator of changes in glycosylation. Upon 8a exposure to CCRF-CEM cells, a significant decrease in high-mannose-type glycans was observed. Different expressions of oligosaccharyltransferase subunits appear to play a key functional role in regulating the hypoglycosylation and contribute to the action mechanism of 8a. Taken together our findings suggest that glycosylation is strongly affected by therapeutic potency and can be used as possible biomarkers for monitoring toxicity and antitumor activity of 8a.
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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. PLoS One 2013
2016Co-Authors: Yini Wang, Dan Gao, Zhe Chen, Chunmei Gao, Deliang Cao, Feng Liu, Hongxia Liu, Yuyang JiangAbstract: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 togethe
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exposure of ccrf cem cells to Acridone Derivative 8a triggers tumor death via multiple mechanisms
Proteomics, 2016Co-Authors: Yini Wang, Dan Gao, Chunmei Gao, Deliang Cao, Hongxia Liu, Bizhu Chu, Yuyang JiangAbstract:A newly synthesized Acridone Derivative 8a shows potent antitumor activity against CCRF-CEM leukemia cells. Herein, the first proteomic study of 8a effects in CCRF-CEM cells was performed by 2D nano-LC-ESI-MS/MS to better understand the mechanisms of action of 8a. Data analyses based on PLGS, STRING, Cytoscape, and database for annotation, visualization, and integrated discovery identified 55 proteins that were differentially expressed in response to 8a exposure. Multiple cellular pathways were affected, including chromatin organization, energy metabolism, DNA repair, oxidative-stress, and apoptosis. The changes in protein expression were further verified for PKM2. Moreover, 8a lowered down the expression of HEX and PFK-1. Lactate production was decreased in 8a-treated cells, indicating suppression of glycolysis. The elevated XRCC6 and decreased histone expression levels suggested increased DNA damage in 8a-treated cells, which was confirmed by the increased γ-H2AX foci. Molecular docking of 8a with DNA demonstrated direct interactions of 8a with DNA through three hydrogen bonds and four π-π interactions, potentially explaining the mode of action that 8a damaged to DNA. The differential protein profiling and dysfunction of metabolic pathways induced by 8a provide novel insights into the potential action mechanisms of 8a.
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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
PLOS ONE, 2013Co-Authors: Yini Wang, Dan Gao, Zhe Chen, Chunmei Gao, Deliang Cao, Feng Liu, Hongxia Liu, Yuyang JiangAbstract: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.
Dan Gao - One of the best experts on this subject based on the ideXlab platform.
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comparative proteomic analysis of histone modifications upon Acridone Derivative 8a induced ccrf cem cells by data independent acquisition
Journal of Proteome Research, 2020Co-Authors: Yini Wang, Dan Gao, Bowen Zhong, Dongdong Zhan, Mingwei Liu, Yi Wang, Jun QinAbstract:The lead compound Acridone Derivative 8a showed potent antiproliferative activity by inducing DNA damage through direct stacking with DNA bases and triggering ROS in CCRF-CEM cells. To define the chromatin alterations during DNA damage sensing and repair, a detailed quantitative map of single and coexisting histone post-translational modifications (PTMs) in CCRF-CEM cells affected by 8a was performed by the Data Independent Acquisition (DIA) method on QE-plus. A total of 79 distinct and 164 coexisting histone PTMs were quantified, of which 16 distinct histone PTMs were significantly altered when comparing 8a-treated cells with vehicle control cells. The changes in histone PTMs were confirmed by Western blotting analysis for three H3 and one H4 histone markers. The up-regulated dimethylation on H3K9, H3K36, and H4K20 implied that CCRF-CEM cells might accelerate DNA damage repair to counteract the DNA lesion induced by 8a, which was verified by an increment in the 53BP1 foci localization at the damaged DNA. Most of the significantly altered PTMs were involved in transcriptional regulation, including down-regulated acetylation on H3K18, H3K27, and H3K122, and up-regulated di- and trimethylation on H3K9 and H3K27. This transcription-silencing phenomenon was associated with G2/M cell cycle arrest after 8a treatment by flow cytometry. This study shows that the DIA proteomics strategy provides a sensitive and accurate way to characterize the coexisting histone PTMs changes and their cross-talk in CCRF-CEM cells after 8a treatment. Specifically, histone PTMs rearrange transcription-silencing, and cell cycle arrest DNA damage repair may contribute to the mechanism of epigenetic response affected by 8a.
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combing metabolomics with bioanalysis methods to study the antitumor mechanism of the new Acridone Derivative 8q on ccrf cem cells 8q induced mitochondrial mediated apoptosis and targeted the pi3k akt foxo1 pathway
Journal of Pharmaceutical and Biomedical Analysis, 2018Co-Authors: Ning Wang, Dan Gao, Feng Liu, Hongxia Liu, Bin Zhang, Feng Jin, Yuyang JiangAbstract:Abstract A novel Acridone Derivative, N-(2-(dimethylamino)ethyl)-1-((3-methoxybenzyl)amino)-5- nitro-9-oxo-9,10-dihydro-acridine-4-carboxamide (8q), which was synthesized in our lab, showed potent anti-leukaemia activity against CCRF-CEM cells. Moreover, in silico predictions showed that 8q conformed to the rule of five and displayed low toxicity. However, the mechanism of anti-leukaemia action remains unclear. The aim of this research was to reveal the probable anti-leukaemia mechanism of 8q on CCRF-CEM cells. Flow cytometry assay demonstrated that 8q induced apoptosis. The expression of caspase family proteins results showed that 8q could only promote cleaved caspase-3, 7 and 9 expressions without affecting cleaved caspase-8 protein, hinting that 8q induced mitochondrial-mediated apoptosis. Further, we detected 3 indicators of mitochondrial lesions, including increased of Cyt-C release, with a decrease in MMP and ATP levels. Next, metabolomics were introduced to assist in the research of the anti-leukaemia mechanism of 8q. The metabolomics results showed that 100 nM 8q could increase the level of GSH, and decrease its oxidation products. These indicated 8q could influence the ROS, which derived by mitochondria. Then we examined the effect of 8q on intracellular ROS levels. What is particularly interesting is that 8q inhibited cell ROS stress at low concentration and stimulated ROS stress at high concentration. The pro-apoptosis mechanisms of 8q were then explored. 8q significantly decreased anti-apoptotic proteins Bcl-2 and Bcl-xL expression, whereas it up-regulated the pro-apoptotic proteins Bax, Bak, Bad, Bik and Puma expression. In addition, 8q dramatically inhibited the expression of FASN, which is related to fatty acid metabolism. Furthermore, PI3K, AKT and FOXO1 were inactivated, and the expression of total AKT was also inhibited by 8q treatment, which promoted intrinsic apoptosis. In conclusion, these findings demonstrate that 8q can induce mitochondrial lesions and promote mitochondrial-mediated pathway apoptosis by regulating the expression of Bcl-2 family proteins and inhibiting the activity of the PI3K/AKT/FOXO1 signaling pathway.
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changes in cellular glycosylation of leukemia cells upon treatment with Acridone Derivatives yield insight into drug action
Proteomics, 2016Co-Authors: Yini Wang, Dan Gao, Hongxia Liu, Dayoung Park, Ace G Galermo, Carlito B LebrillaAbstract:A new Acridone Derivative 2-aminoacetamido-10-(3, 5-dimethoxy)-benzyl-9(10H)-Acridone hydrochloride (8a) has been shown to have potent antitumor activity. In order to understand the underlying action mechanism of 8a, three compounds of the same class with structures optimized step-by-step, 9(10H)-Acridone (A), 10-(3,5-dimethoxy) benzyl-9(10H)-Acridone (I) and 8a, were exposed to CCRF-CEM leukemia cell to determine the N-glycosylation changes using the microfluidic HPLC-chip-TOF MS platform. N-Glycans from whole cell lysates (WCL) and cell membranes (CM) were analyzed using isomer-sensitive chip-based porous graphitized carbon nano-LC/MS. A total of 223 N-glycan compositions and 398 N-glycan compounds were identified. Comparison of the two analyses showed that more apparent changes were observed in the CM compared with WCL, suggesting that CM may be a more sensitive indicator of changes in glycosylation. Upon 8a exposure to CCRF-CEM cells, a significant decrease in high-mannose-type glycans was observed. Different expressions of oligosaccharyltransferase subunits appear to play a key functional role in regulating the hypoglycosylation and contribute to the action mechanism of 8a. Taken together our findings suggest that glycosylation is strongly affected by therapeutic potency and can be used as possible biomarkers for monitoring toxicity and antitumor activity of 8a.
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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. PLoS One 2013
2016Co-Authors: Yini Wang, Dan Gao, Zhe Chen, Chunmei Gao, Deliang Cao, Feng Liu, Hongxia Liu, Yuyang JiangAbstract: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 togethe
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exposure of ccrf cem cells to Acridone Derivative 8a triggers tumor death via multiple mechanisms
Proteomics, 2016Co-Authors: Yini Wang, Dan Gao, Chunmei Gao, Deliang Cao, Hongxia Liu, Bizhu Chu, Yuyang JiangAbstract:A newly synthesized Acridone Derivative 8a shows potent antitumor activity against CCRF-CEM leukemia cells. Herein, the first proteomic study of 8a effects in CCRF-CEM cells was performed by 2D nano-LC-ESI-MS/MS to better understand the mechanisms of action of 8a. Data analyses based on PLGS, STRING, Cytoscape, and database for annotation, visualization, and integrated discovery identified 55 proteins that were differentially expressed in response to 8a exposure. Multiple cellular pathways were affected, including chromatin organization, energy metabolism, DNA repair, oxidative-stress, and apoptosis. The changes in protein expression were further verified for PKM2. Moreover, 8a lowered down the expression of HEX and PFK-1. Lactate production was decreased in 8a-treated cells, indicating suppression of glycolysis. The elevated XRCC6 and decreased histone expression levels suggested increased DNA damage in 8a-treated cells, which was confirmed by the increased γ-H2AX foci. Molecular docking of 8a with DNA demonstrated direct interactions of 8a with DNA through three hydrogen bonds and four π-π interactions, potentially explaining the mode of action that 8a damaged to DNA. The differential protein profiling and dysfunction of metabolic pathways induced by 8a provide novel insights into the potential action mechanisms of 8a.
C. Dumontet - One of the best experts on this subject based on the ideXlab platform.
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The Acridone Derivative MBLI-87 sensitizes breast cancer resistance protein-expressing xenografts to irinotecan.
European Journal of Cancer, 2011Co-Authors: O. Arnaud, A. Boumendjel, A. Gèze, M. Honorat, E. L. Matera, J. Guitton, W. D. Stein, S. E. Bates, P. Falson, C. DumontetAbstract:The breast cancer resistance protein ABCG2 confers cellular resistance to irinotecan (CPT-11) and its active metabolite SN-38. We utilised ABCG2-expressing xenografts as a model to evaluate the ability of a non-toxic ABCG2 inhibitor to increase intracellular drug accumulation. We assessed the activity of irinotecan in vivo in SCID mice: irinotecan completely inhibited the development of control pcDNA3.1 xenografts, whilst only delaying the growth of ABCG2-expressing xenografts. Addition of MBLI-87, an Acridone Derivative inhibitor, significantly increased the irinotecan effect against the growth of ABCG2-expressing xenografts. In vitro, MBLI-87 was as potent as GF120918 against ABCG2-mediated irinotecan efflux, and additionally was specific for ABCG2. A significant sensitisation to irinotecan was achieved despite the fact that doses remained well below the maximum tolerated dose (due to the rather limited solubility of MBLI-87). This suggested that MBLI-87 is an excellent candidate to prevent drug efflux by ABCG2, without altering plasma concentrations of irinotecan and SN-38 after IP (intra-peritoneal) injections. This could constitute a useful strategy to improve drug pharmacology, to facilitate drug penetration into normal tissue compartments protected by ABCG2, and potentially to reverse drug resistance in cancer cells.
Hongxia Liu - One of the best experts on this subject based on the ideXlab platform.
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combing metabolomics with bioanalysis methods to study the antitumor mechanism of the new Acridone Derivative 8q on ccrf cem cells 8q induced mitochondrial mediated apoptosis and targeted the pi3k akt foxo1 pathway
Journal of Pharmaceutical and Biomedical Analysis, 2018Co-Authors: Ning Wang, Dan Gao, Feng Liu, Hongxia Liu, Bin Zhang, Feng Jin, Yuyang JiangAbstract:Abstract A novel Acridone Derivative, N-(2-(dimethylamino)ethyl)-1-((3-methoxybenzyl)amino)-5- nitro-9-oxo-9,10-dihydro-acridine-4-carboxamide (8q), which was synthesized in our lab, showed potent anti-leukaemia activity against CCRF-CEM cells. Moreover, in silico predictions showed that 8q conformed to the rule of five and displayed low toxicity. However, the mechanism of anti-leukaemia action remains unclear. The aim of this research was to reveal the probable anti-leukaemia mechanism of 8q on CCRF-CEM cells. Flow cytometry assay demonstrated that 8q induced apoptosis. The expression of caspase family proteins results showed that 8q could only promote cleaved caspase-3, 7 and 9 expressions without affecting cleaved caspase-8 protein, hinting that 8q induced mitochondrial-mediated apoptosis. Further, we detected 3 indicators of mitochondrial lesions, including increased of Cyt-C release, with a decrease in MMP and ATP levels. Next, metabolomics were introduced to assist in the research of the anti-leukaemia mechanism of 8q. The metabolomics results showed that 100 nM 8q could increase the level of GSH, and decrease its oxidation products. These indicated 8q could influence the ROS, which derived by mitochondria. Then we examined the effect of 8q on intracellular ROS levels. What is particularly interesting is that 8q inhibited cell ROS stress at low concentration and stimulated ROS stress at high concentration. The pro-apoptosis mechanisms of 8q were then explored. 8q significantly decreased anti-apoptotic proteins Bcl-2 and Bcl-xL expression, whereas it up-regulated the pro-apoptotic proteins Bax, Bak, Bad, Bik and Puma expression. In addition, 8q dramatically inhibited the expression of FASN, which is related to fatty acid metabolism. Furthermore, PI3K, AKT and FOXO1 were inactivated, and the expression of total AKT was also inhibited by 8q treatment, which promoted intrinsic apoptosis. In conclusion, these findings demonstrate that 8q can induce mitochondrial lesions and promote mitochondrial-mediated pathway apoptosis by regulating the expression of Bcl-2 family proteins and inhibiting the activity of the PI3K/AKT/FOXO1 signaling pathway.
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changes in cellular glycosylation of leukemia cells upon treatment with Acridone Derivatives yield insight into drug action
Proteomics, 2016Co-Authors: Yini Wang, Dan Gao, Hongxia Liu, Dayoung Park, Ace G Galermo, Carlito B LebrillaAbstract:A new Acridone Derivative 2-aminoacetamido-10-(3, 5-dimethoxy)-benzyl-9(10H)-Acridone hydrochloride (8a) has been shown to have potent antitumor activity. In order to understand the underlying action mechanism of 8a, three compounds of the same class with structures optimized step-by-step, 9(10H)-Acridone (A), 10-(3,5-dimethoxy) benzyl-9(10H)-Acridone (I) and 8a, were exposed to CCRF-CEM leukemia cell to determine the N-glycosylation changes using the microfluidic HPLC-chip-TOF MS platform. N-Glycans from whole cell lysates (WCL) and cell membranes (CM) were analyzed using isomer-sensitive chip-based porous graphitized carbon nano-LC/MS. A total of 223 N-glycan compositions and 398 N-glycan compounds were identified. Comparison of the two analyses showed that more apparent changes were observed in the CM compared with WCL, suggesting that CM may be a more sensitive indicator of changes in glycosylation. Upon 8a exposure to CCRF-CEM cells, a significant decrease in high-mannose-type glycans was observed. Different expressions of oligosaccharyltransferase subunits appear to play a key functional role in regulating the hypoglycosylation and contribute to the action mechanism of 8a. Taken together our findings suggest that glycosylation is strongly affected by therapeutic potency and can be used as possible biomarkers for monitoring toxicity and antitumor activity of 8a.
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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. PLoS One 2013
2016Co-Authors: Yini Wang, Dan Gao, Zhe Chen, Chunmei Gao, Deliang Cao, Feng Liu, Hongxia Liu, Yuyang JiangAbstract: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 togethe
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exposure of ccrf cem cells to Acridone Derivative 8a triggers tumor death via multiple mechanisms
Proteomics, 2016Co-Authors: Yini Wang, Dan Gao, Chunmei Gao, Deliang Cao, Hongxia Liu, Bizhu Chu, Yuyang JiangAbstract:A newly synthesized Acridone Derivative 8a shows potent antitumor activity against CCRF-CEM leukemia cells. Herein, the first proteomic study of 8a effects in CCRF-CEM cells was performed by 2D nano-LC-ESI-MS/MS to better understand the mechanisms of action of 8a. Data analyses based on PLGS, STRING, Cytoscape, and database for annotation, visualization, and integrated discovery identified 55 proteins that were differentially expressed in response to 8a exposure. Multiple cellular pathways were affected, including chromatin organization, energy metabolism, DNA repair, oxidative-stress, and apoptosis. The changes in protein expression were further verified for PKM2. Moreover, 8a lowered down the expression of HEX and PFK-1. Lactate production was decreased in 8a-treated cells, indicating suppression of glycolysis. The elevated XRCC6 and decreased histone expression levels suggested increased DNA damage in 8a-treated cells, which was confirmed by the increased γ-H2AX foci. Molecular docking of 8a with DNA demonstrated direct interactions of 8a with DNA through three hydrogen bonds and four π-π interactions, potentially explaining the mode of action that 8a damaged to DNA. The differential protein profiling and dysfunction of metabolic pathways induced by 8a provide novel insights into the potential action mechanisms of 8a.
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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
PLOS ONE, 2013Co-Authors: Yini Wang, Dan Gao, Zhe Chen, Chunmei Gao, Deliang Cao, Feng Liu, Hongxia Liu, Yuyang JiangAbstract: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.
