Journal of Oncology
·
2022
·
IF 4.501
Li Zheng,Yu Wu,Fu Wang,Hui Shi,Bo Xu,Aihua Yang
Objective. To study the pharmacological activity and the mechanism of action of natural compounds derived from 6,7-dimethoxycoumarin on the differentiation of human chronic myeloid leukemia K562 cells. Methods. We use MTT assay (Sigma-Aldrich, USA) to detect cell viability; use flow cytometry to analyze DNA content for cell cycle analysis; use benzidine staining to synthesize hemoglobin to determine K562 cell differentiation; use western blot analysis and qPCR to detect the expression levels of FOX03, P27, CDK4, and their phosphorylation; and use the AOBS laser scanning confocal system (Leica, Wetzlar, Germany) to analyze and quantify the number of positive green spots. The statistical methods used are one-way analysis of variance (ANOVA) and Dunnett’s test to analyze within and between groups. Results. In order to explore the effect of 6,7-dimethoxycoumarin on the differentiation of K562 cell erythrocytes, it was concluded that 6,7-dimethoxycoumarin promotes the differentiation of K562 cell erythrocytes; the proliferation of K562 cells was detected by MTT method, and the results showed that 6,7-dimethoxycoumarin can inhibit the proliferation of K562 cells; to evaluate the effect of 6,7-dimethoxycoumarin on the proliferation of K562 cells, the results showed that 6,7-dimethoxycoumarin increased the expression of FOXO3, P27, CDK4, and CDK65, and decreased the phosphorylation of CDK4 and CDK6 proteins. To further explore the effect of knocking out FOXO3 on cell differentiation, the results show that 6,7-dimethoxycoumarin can reduce the differentiation and proliferation of K562 cells by increasing the expression of FOXO3. Conclusion. This study extended the understanding of the pharmacological activity of 6,7-dimethoxycoumarin and may provide a potential new target for the treatment of chronic myelogenous leukemia. However, we still need to further study the specific molecular capabilities of 6.7 dimethylcoumarin to understand their possible capture mechanism.
研究领域:
肿瘤学
·
血液学
·
分子生物学
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药理学
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DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-13
·
IF 5.228
Wu Xunxun,Chen Xiaofei,Jia Dan,Cao Yan,Gao Shouhong,Guo Zhiying,Zerbe Philipp,Chai Yifeng,Diao Yong,Zhang Lei
Traditional Chinese Medicine (TCM) has been developed for thousands of years and has formed an integrated theoretical system based on a large amount of clinical practice. However, essential ingredients in TCM herbs have not been fully identified, and their precise mechanisms and targets are not elucidated. In this study, a new strategy combining comprehensive two-dimensional K562/cell membrane chromatographic system and in silico target identification was established to characterize active components from Indigo naturalis , a famous TCM herb that has been widely used for the treatment of leukemia in China, and their targets. Three active components, indirubin, tryptanthrin and isorhamnetin, were successfully characterized and their anti-leukemia effects were validated by cell viability and cell apoptosis assays. Isorhamnetin, with undefined cancer related targets, was selected for in silico target identification. Proto-oncogene tyrosine-protein kinase (Src) was identified as its membrane target and the dissociation constant (Kd) between Src and isorhamnetin was 3.81 μM. Furthermore, anti-leukemia effects of isorhamnetin were mediated by Src through inducing G2/M cell cycle arrest. The results demonstrated that the integrated strategy could efficiently characterize active components in TCM and their targets, which may bring a new light for a better understanding of the complex mechanism of herbal medicines.
研究领域:
药理学
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肿瘤学
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中医
·
色谱学
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生物信息学
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DOI
PubMed
高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
·
2016
·Vol. 22
·期 50
·18001-18008
·
IF 5.771
Jing Liu,Meirong Cui,Li Niu,Hong Zhou,Shusheng Zhang
Graphical Time for gold : A smart electrochemical aptamer biosensor for K562 leukemia cancer cells with enhanced peroxidase-like properties that shows a good performance in selectivity and sensitivity is presented. The biosensor employs a new graphene-family ternary composite with prickly Au nanoflowers on its surface. Graphene composites with hemin and gold nanoparticles show a better performance for hydrogen peroxide decomposition compared to that of the three components alone or duplex/hybrid complexes. Our previous studies showed that the morphology of the Au nanoparticles may greatly influence the catalytic activity of graphene-family peroxidase mimics. Recently, we found that Au nanoflowers could grow in situ and form on the surface of hemin/RGO (reduced graphene oxide). The prickly morphology of this Au nanoflower brought a higher catalytic ability with enhanced kinetic parameters than traditional Au nanoparticles that showed a smooth surface. Therefore, based on this discovery, a smart electrochemical aptamer biosensor for K562 leukemia cancer cells was further presented with good performance in selectivity and sensitivity attributed to the excellent mimetic peroxidase catalytic activity of this newly synthesized Au nanoflower decorated graphene–hemin composite (H-RGO-Au NFs).
研究领域:
生物传感器
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癌症研究
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纳米技术
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电化学
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DOI
PubMed
高影响因子
ELECTROCHEMISTRY COMMUNICATIONS
·
2012
·
IF 4.859
Yuehong Pang,Zhaoqiang Ge,Yong Liu,Xiaofang Shen
Covalently conjugating folate on Au surface was achieved via click chemistry, copper (I)-catalyzed azide-alkyne cycloaddition reaction. Human leukemia K562 cells were used as a model system to investigate capturing cancer cells by folate-targeted electrode. Scanning optical microscopy and electrochemical method were used to monitor the capture of K562 cells on folate-clicked electrode.
研究领域:
生物化学
·
医学工程
·
分子生物学
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产品关联
DOI
高影响因子
JOURNAL OF HETEROCYCLIC CHEMISTRY
·
2017
·Vol. 55
·期 1
·351-359
·
IF 0.893
Xiong-Wei Liu,Jun Yang,Guan-Lian Wang,Yi Gong,Ting-Ting Feng,Xiong-Li Liu,Yu Cao,Ying Zhou,Wei-Cheng Yuan
Described herein is a facile and efficient methodology toward the synthesis of novel convolutamydine A-incorporated β -ionone scaffold 3 from an Aldol addition event of β -ionone to isatins via enamine Et 2 NH catalysis. Products featuring a quaternary carbon center were smoothly obtained in good yields (up to 96% yield). This protocol also represents the first construction of ionone skeleton-fused oxindole molecules, thus leading to new knowledge in the fields of both molecular complexity and diversity-oriented synthesis and the lead compound discovery. Furthermore, their biological activities against human leukemia cells K562 have been preliminarily demonstrated by in vitro assays. The results demonstrated that most of these compounds obtained by this protocol showed comparable with or even much better than the positive control of Cisplatin.
研究领域:
有机化学
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药物化学
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肿瘤学
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产品关联
DOI
高影响因子
FITOTERAPIA
·
2025
·
IF 2.6
Liyuan Shen,Jingwen Xu,Yihai Wang,Jiaming Yao,Xiangjiu He
Chronic myeloid leukemia (CML) is a myeloproliferative tumor, which is prone to drug resistance during treatment. Previous studies have indicated that Ficus altissima Blume exhibits potential antitumor properties, with 5,7,2′-trihydroxy-4′-methoxy-6-(3-hydroxy-3-methylbutyl)-isoflavone (TMI) as its main active component. However, the antitumour activity of TMI and its underlying mechanisms remain unexplored. This study investigated the anti-proliferative effects of TMI on adriamycin (ADR)-resistant leukemia K562 cells (K562/ADR cells) and the mechanism of overcoming multidrug resistance (MDR). The findings demonstrated that TMI significantly downregulated P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) expression. It was confirmed that TMI triggered caspase-dependent apoptosis in K562/ADR and K562 cells. While reactive oxygen species accumulation and PI3K/AKT/mTOR mediated TMI's effect in K562 cells, these pathways were irrelevant to its apoptosis induction and MDR overcoming in K562/ADR cells. Further research found that the nuclear factor erythroid 2-related factor 2 (Nrf2) expression was significantly suppressed by TMI treatment. In contrast, exposure to the Nrf2 agonist tert-butylhydroquinone resulted in upregulation of P-gp and BCRP protein levels in K562/ADR cells. This suggests that TMI's overcoming of K562/ADR cell drug resistance is associated with Nrf2 degradation. Finally, molecular docking analysis and cellular thermal shift assay experiments showed that TMI exerted anti-drug resistance effect by directly binding to Nrf2 protein. Collectively, TMI overcomes K562/ADR cell resistance primarily through targeting and inhibiting Nrf2 protein and decreasing drug efflux protein expression, ultimately promoting cell death. These results highlight TMI's potential as a drug-resistant leukemia therapy, while also suggesting that developing Nrf2-targeted inhibitors may represent a novel strategy for overcoming tumor drug resistance.
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PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2011
·Vol. 401
·期 7
·2143-2152
·
IF 3.841
Deng Bin,Wang Zhiming,Song Jian,Xiao Yuxiu,Chen Dan,Huang Jun
The doxorubicin (DOX) uptake in single human leukemia K562 cells with changes in both drug dosage and exposure period was studied using capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF) detection. The cells were treated with DOX at different concentrations (1, 3, 10, 20, 30, and 50 μM) and for different exposure times (1, 3, 5, 24, and 48 h). At least 20 cells were analyzed for each DOX-treated cell population. A marked heterogeneity in DOX uptake among single cells was observed, because the relative standard deviation of the uptake of DOX by single cells ranged from 24.0% to 61.1% within each cell population. The cell-to-cell heterogeneity in DOX uptake first decreased and then became constant with increasing drug concentration, but it did not exhibit regular variation with increasing exposure time. The mean DOX uptake was a linear function of drug concentration ( r ≥ 0.9667). In terms of the correlation with exposure time, the mean DOX uptake reached its maximum at 3 h for the cell populations treated with 1–10 μM DOX, while it kept increasing during 48 h exposure of cell populations to 20–50 μM DOX. Because it eliminates DOX fluorescence quenching and sample loss, the CE-LIF method directly detects the true DOX uptake by single cells, and thus presents accurate information on both the cell-to-cell heterogeneity in DOX uptake and the patterns of DOX uptake in K562 cells as functions of drug concentration and exposure time.
CE-LIF analysis of DOX uptake in single human leukemia K562 cells. a DOX uptakes of single K562 cells treated with 1 μM DOX for 3 h; The RSD% for the DOX uptake of single K562 cells as functions of b the extracellular DOX concentration and c the exposure time; Mean DOX uptake of single K562 cells as functions of d the extracellular DOX concentration and e the exposure time
研究领域:
药理学
·
肿瘤学
·
分析化学
·
细胞生物学
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DOI
PubMed
高影响因子
Oncotarget
·
2015
·
IF 6.359
Ping Song,Li Ye,Jiajun Fan,Yubin Li,Xian Zeng,Ziyu Wang,Shaofei Wang,Guoping Zhang,Ping Yang,Zhonglian Cao,Dianwen Ju
The antitumor enzyme asparaginase, which targets essential amino acid L-asparagine and catalyzes it to L-aspartic acid and ammonia, has been used for years in the treatment of acute lymphoblastic leukemia (ALL), subtypes of myeloid leukemia and T-cell lymphomas, whereas the anti-chronic myeloid leukemia (CML) effect of asparaginase and its underlying mechanism has not been completely elucidated. We have shown here that asparaginase induced significant growth inhibition and apoptosis in K562 and KU812 cells. Apart from induction of apoptosis, we reported for the first time that asparaginase induced autophagic response in K562 and KU812 cells as evidenced by the formation of autophagosome, microtubule-associated protein light chain 3 (LC3)-positive autophagy-like vacuoles, and the upregulation of LC3-II. Further study suggested that the Akt/mTOR (mammalian target of rapamycin) and Erk (extracellular signal-regulated kinase) signaling pathway were involved in asparaginase-induced autophagy in K562 cells. Moreover, blocking autophagy using pharmacological inhibitors LY294002, chloroquine (CQ) and quinacrine (QN) enhanced asparaginase-induced cell death and apoptosis, indicating the cytoprotective role of autophagy in asparaginase-treated K562 and KU812 cells. Together, these findings provide a rationale that combination of asparaginase anticancer activity and autophagic inhibition might be a promising new therapeutic strategy for CML.
研究领域:
肿瘤学
·
血液学
·
分子生物学
·
细胞生物学
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DOI
PubMed
高影响因子
PLoS One
·
2024
·Vol. 19
·期 8
·e0306043
·
IF 2.9
Yuping Liao,Feng Zhang,Fang Yang,Shijin Huang,Sha Su,Xuemei Tan,Linlin Zhong,Lingjie Deng,Lihong Pang
Background
Haemoglobin H (HbH) disease is caused by a disorder of α-globin synthesis, and it results in a wide range of clinical symptoms. M 6 A methylation modification may be one of the mechanisms of heterogeneity. Therefore, this article explored the role of methyltransferase like 16 (METTL16) in HbH disease.
Method
The results of epigenetic transcriptome microarray were analysed and verified through bioinformatic methods and qRT-PCR, respectively. The overexpression or knock down of METTL16 in K562 cells was examined to determine its role in reactive oxygen species (ROS), cell cycle processes or iron overload. YTH domain family protein 3 (YTHDF3) was knocked down in K562 cells and K562 cells overexpressing METTL16 via siRNA to investigate its function. In addition, haemoglobin expression was detected through benzidine staining. qRT-PCR, WB, methylated RNA Immunoprecipitation (MeRIP) and (RNA Immunoprecipitation) RIP experiments were conducted to explore the mechanism of intermolecular interaction.
Results
METTL16, YTHDF3 and solute carrier family 5 member 3 (SLC5A3) mRNA and the methylation level of SLC5A3 mRNA were downregulated in HbH patients. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA expression was negatively correlated with HGB content among patients with HbH-CS disease. Overexpression of METTL16 increased ROS and intracellular iron contents in K562 cells, changed the K562 cell cycle, reduced hemin-induced haemoglobin synthesis, increased the expressions of SLC5A3 and HBG and increased SLC5A3 mRNA methylation levels. Knockdown of METTL16 reduced ROS and intracellular iron contents in K562 cells. Hemin treatment of K562 cells for more than 14 days reduced the protein expressions of METTL16 and SLC5A3 and SLC5A3 mRNA methylation levels. Knockdown of YTHDF3 rescued the intracellular iron content changes induced by the overexpression of METTL16. The RIP experiment revealed that SLC5A3 mRNA can be enriched by METTL16 antibody.
Conclusion
METTL16 may affect the expression of SLC5A3 by changing its m 6 A modification level and regulating ROS synthesis, intracellular iron and cycle of red blood cells. Moreover, METTL16 possibly affects the expression of haemoglobin through IGF2BP3, which regulates the clinical phenotype of HbH disease.
研究领域:
分子生物学
·
血液学
·
表观遗传学
·
细胞生物学
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DOI
PubMed
高影响因子
RSC Advances
·
2018
·Vol. 8
·期 24
·13103-13111
·
IF 2.936
Jing Zhang,Di Zhang,Xu Hu,Ruiling Liu,Zhonghao Li,Yuxia Luan
Because of the drawbacks of cytarabine (Ara-C) such as poor lipid solubility, deamination inactivation and low oral bioavailability limiting its application by oral administration, herein we propose a novel amphiphilic low molecular weight cytarabine prodrug (PA-Ara) by conjugating palmitic acid (PA) to Ara-C, making it possible to avoid the deamination inactivation by protecting the active 4-amino, as well as improving lipid solubility. Thanks to the rational design, the oil/water partition coefficient (P) of PA-Ara was improved tremendously compared with Ara-C, and the PA-Ara conjugation was stable enough in artificial digestive juice, ensuring that most molecules could be absorbed in the form of the prodrug. Results from an MTT assay conducted to measure the cytotoxicity of Ara-C and PA-Ara to HL60 (acute myeloblastic leukemia cell line) and K562 cells (chronic granulocytic leukemia cell line) showed that PA-Ara had significantly stronger antiproliferation activities than Ara-C. Significantly, we firstly compared the bioavailability of the oral fatty acid chain modified cytarabine prodrug preparation with injection and the relative bioavailability was up to 61.77% for our PA-Ara, which was much superior to that of oral Ara-C solution (3.23%). Overall, these findings make it clear that the PA-Ara suspension has the potential to be a promising new cytarabine oral preparation for leukemia therapy.
研究领域:
药学
·
药物递送系统
·
药理学
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICAL CHROMATOGRAPHY
·
2014
·Vol. 28
·期 10
·1393-1401
·
IF 1.662
Bin Deng,Zhi-Ming Wang,Zi-Hao Zhou,Yi-Meng Liu,Xi-Liang Yang,Jian Song,Yu-Xiu Xiao
Cellular heterogeneity in doxorubicin (DOX) uptake and its relationship with pharmacological effect on cancer cells were quantitatively investigated for the first time. An in vitro experimental model was established by treating human leukemia K562 and breast cancer MCF-7 cells with different schedules of DOX with or without surface P-glycoprotein (P-gp) inhibitor verapamil (VER). The cellular heterogeneity in DOX uptake was quantitatively examined by single-cell analysis using capillary electrophoresis coupled with laser-induced fluorescence detection. The corresponding cytotoxic effect was tested by cellular morphology, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium and flow cytometry assays. The expression of cellular membrane surface P-gp was determined by flow cytometry. Results showed that the cellular heterogeneity exists in DOX uptake. The single-high DOX schedule leads to lower uptake heterogeneity and higher mean drug uptake. The cellular heterogeneity in DOX uptake was found to be negatively correlated with drug cytotoxicity and surface P-gp expression, with r = −0.7680 to ~ −0.9587. VER reduces the cellular variation in DOX uptake, suggesting that surface P-gp may be one of the causes of the cellular heterogeneity in DOX uptake. This research demonstrates the importance of quantitative study of cellular heterogeneity in drug uptake and its potential application in drug schedule design, response prediction and therapy modulation. Copyright © 2014 John Wiley & Sons, Ltd.
研究领域:
药理学
·
肿瘤学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
Food & Function
·
2022
·Vol. 13
·期 4
·2200-2215
·
IF 6.317
Yi Wang,Jingwen Xu,Yihai Wang,Limin Xiang,Xiangjiu He
Multidrug resistance (MDR) is a major cause of chemotherapy failure. Adriamycin (ADR) has been widely used to treat cancer, however, as a substrate of the adenosine triphosphate binding cassette (ABC) transporter, it is easy to develop drug resistance during the treatment. Here, we demonstrated that steroidal saponin S-20 isolated from the berries of black nightshade has comparable cytotoxicity in ADR-sensitive and resistant K562 cell lines. Autophagy is generally considered to be a protective mechanism to mediate MDR during treatment. However, we found that S-20-induced cell death in K562/ADR is associated with autophagy. We further explored the underlying mechanisms and found that S-20 induces caspase-dependent apoptosis in ADR-sensitive and resistant K562 cell lines. Most importantly, S-20-induced autophagy activates the ERK pathway and then inhibits the expression of drug resistance protein, which is the main reason to overcome K562/ADR resistance, rather than apoptosis. Taken together, our findings emphasize that S-20 exerts anti-multidrug resistance activity in K562/ADR cells through autophagic cell death and ERK activation, which may be considered as an effective strategy.
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PubMed
高影响因子
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