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1.
Chin J Nat Med ; 17(10): 768-777, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31703757

ABSTRACT

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple kinds of cancers including non-small cell lung cancer (NSCLC). CIP2A plays an 'oncogenic nexus' to participate in the tumorigenesis and chemoresistance in several cancer types. AKT and mTORC1 overactivation are detected in NSCLC and many other cancers. Previous studies found that the CIP2A/AKT/mTOR pathway controls cell growth, apoptosis, autophagy process. Polyphyllin I (PPI) and polyphyllin VII (PPVII) are natural components extracted from Paris polyphylla that display anti-cancer properties. In the present study, we investigated whether PPI and PPVII can be used in the cisplatin (DDP)-resistant human NSCLC cell line A549/DDP. Results demonstrated that PPI and PPVII treatment significantly suppressed A549/DDP cell proliferation, migration, invasion and EMT, induced apoptosis and autophagy. Further examination of the mechanism revealed that the PPI and PPVII significantly upregulated the p53, induced caspase-dependent apoptosis and suppressed the CIP2A/AKT/mTOR pathway. The activation of autophagy was mediated through PPI and PPVII induced inhibition of mTOR. We propose that PPI and PPVII might be developed as candidate drugs for DDP-resistant NSCLC.


Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Diosgenin/analogs & derivatives , Drug Resistance, Neoplasm , Drugs, Chinese Herbal/pharmacology , Lung Neoplasms/metabolism , Saponins/pharmacology , Signal Transduction/drug effects , A549 Cells , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/physiopathology , Cell Proliferation/drug effects , Cisplatin/pharmacology , Diosgenin/pharmacology , Drug Resistance, Neoplasm/drug effects , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/physiopathology , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Up-Regulation/drug effects
2.
Asian Pac J Cancer Prev ; 15(12): 4871-6, 2014.
Article in English | MEDLINE | ID: mdl-24998556

ABSTRACT

BACKGROUND: We sought to evaluate the role of tumor associated macrophages (TAMs) on the promotion of coal tar pitch extract (CTPE)-induced tumorigenesis of human bronchial epithelial cells (BEAS-2B) and tumor metastasis in nude mice, and related mechanisms. MATERIALS AND METHODS: BEAS-2B cells were first treated with 2.4 mg/mL CTPE for 72 hours. After removal of CTPE, the cells were continuously cultured and passaged using trypsin-EDTA. THP-1 cells were used as macrophage-like cells. BEAS-2B cells under different conditions (n=6/ group) were injected into the back necks of nude mice, and alterations of tumor xenograft growth, indicative of tumorigenicity, and tumor metastasis were determined. Pathological changes (tumor nests and microvascular lesions) of HE-stained tumor tissues were also evaluated. The expression of AP-1(c-Jun) in xenografts and metastatic tumors was determined using immunohistochemistry. RESULTS: Tumor size and weight in nude mice transplanted with the mixture of CTPE-induced passage 30 BEAS-2B and THP-1 cells (2:1) were increased compared to those from the CTPE-treated BEAS-2B cells at passage 30 alone at different observation time points. Tumor metastasis to lymph nodes and liver was only detected after transplantation of a mixture the two kinds of cells. The numbers of tumor nests and microvascular lesions, and the expression levels of AP-1 (c-Jun) in tumors from the mixture of two kinds of cells were increased apparently in contrast to those in tumor from the CTPE-treated BEAS-2B cells of passage 30 alone. In addition, there was positive correlation between AP-1 (c-Jun) expression level and the number of microvascular lesions, or between AP-1 (c-Jun) expression level and tumor metastasis in these two groups. CONCLUSIONS: TAMs not only facilitate tumorigenesis transformation of CTPE-induced BEAS-2B cells, but also promote tumor growth, angiogenesis and metastasis in nude mice in vivo, which may be mediated by AP-1.


Subject(s)
Bronchi/pathology , Cell Transformation, Neoplastic/pathology , Coal Tar/adverse effects , Liver Neoplasms/secondary , Lung Neoplasms/pathology , Macrophages/pathology , Transcription Factor AP-1/metabolism , Animals , Bronchi/drug effects , Bronchi/metabolism , Cell Transformation, Neoplastic/metabolism , Cells, Cultured , Complex Mixtures/adverse effects , Humans , Immunoenzyme Techniques , Liver Neoplasms/etiology , Liver Neoplasms/metabolism , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Lymphatic Metastasis , Macrophages/drug effects , Macrophages/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/pathology
3.
Article in Chinese | MEDLINE | ID: mdl-22804928

ABSTRACT

OBJECTIVE: To study the effects of monocyte-macrophages (THP-1) in malignant transformation of human bronchial epithelial cells (BEAS-2B) cells induced by coal tar pitch (CTP) and the expression of TNF-α in the process of the cell malignant transformation. METHODS: BEAS-2B cells and THP-1 Cells were divided into four groups: coal tar pitch (CTP) group, benzo(a)pyrene [B(a)P] group, dimethyl sulfoxide (DMSO) group, BEAS-2B and THP-1 co-culture (co-culture group) group. Carcinogenesis model was established. The soft agar colony formation, chromosome aberrations and cell cycle tests were used to detect the cellular malignant transformation. The ELISA assay was utilized to measure the levels of TNF-α in the supernatant of CTP group and co-culture group. RESULTS: The chromosome number abnormalities could be observed in early stage of the experiment (the 10th generation cells), which showed the increased ratio of aneuploid to polyploid, and the decreased number of diploid. The colony formation rate of co-culture group (the 20th generation cells) was 17.63‰ ± 0.97‰, which was significantly higher than that (13.94‰ ± 0.84‰) of CTP group and that (12.96‰ ± 1.62‰) of B(a)P group (P < 0.05). The proportion of S phase cells in the co-culture group was 44.49% ± 0.68%, which was significantly higher than that (38.19% ± 1.26%) of CTP group and that (36.41% ± 1.19%) of B(a)P group (P < 0.05). The TNF-α level in the co-culture group was significantly higher than that in CTP group (P = 0.001). CONCLUSION: Monocyte-Macrophages can accelerate the malignant transformation of BEAS-2B cells induced by CTP and increase the expression level of TNF-α.


Subject(s)
Cell Transformation, Neoplastic/chemically induced , Coal Tar/toxicity , Epithelial Cells/drug effects , Macrophages/cytology , Monocytes/cytology , Bronchi/cytology , Cell Line , Coculture Techniques , Epithelial Cells/cytology , Epithelial Cells/pathology , Humans , Tumor Necrosis Factor-alpha/metabolism
4.
Drug Deliv ; 18(4): 265-71, 2011 May.
Article in English | MEDLINE | ID: mdl-21091387

ABSTRACT

The mechanism for anti-tumor activity of oridonin (ORI) nanosuspension, prepared by the high pressure homogenization method, was studied using MCF-7 human breast carcinoma cells in vitro. MTT assay, observation of morphologic changes, flow cytometric analysis, and western blot analysis indicated that ORI nanosuspension could significantly intensify the in vitro anti-tumor activity to MCF-7 cells, as compared with ORI solution. Furthermore, ORI nanosuspension induced G2/M stage proliferation arrest and apoptosis in MCF-7 cells depending on its concentration. In addition, western blot analysis indicated that the pro-caspase-3 protein was not cleaved into the activated form and the expression of anti-apoptotic Bcl-2 protein decreased, on the contrary, the expression of pro-apoptotic Bax protein increased in a dose-dependent manner in ORI nanosuspension-treated cells. These observations indicated that the anti-tumor activity of ORI nanosuspension was intensified by cell-cycle arrest and apoptosis induction.


Subject(s)
Apoptosis/drug effects , Breast Neoplasms/drug therapy , Diterpenes, Kaurane/administration & dosage , Nanoparticles/administration & dosage , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Caspase 3/genetics , Caspase 3/metabolism , Cell Division/drug effects , Cell Line, Tumor , Diterpenes, Kaurane/chemistry , Dose-Response Relationship, Drug , Female , G2 Phase/drug effects , Humans , Nanoparticles/chemistry , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Suspensions/administration & dosage , Suspensions/chemistry , bcl-2-Associated X Protein/genetics , bcl-2-Associated X Protein/metabolism
5.
Drug Deliv ; 17(1): 11-8, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19941406

ABSTRACT

Nanostructured lipid carriers (NLC) are a new generation of lipid nanoparticles, which are produced by controlled mixing of solid lipids with spatially incompatible liquid lipids leading to special nanostructures with improved drug incorporation and release properties. In this study, silybin-loaded nanostructured lipid carriers with various liquid lipid content were successfully prepared by the method of emulsion evaporation at a high temperature and solidification at a low temperature. The size and morphology of nanoparticles were significantly influenced by the liquid lipid content. As the liquid lipid content increased to 20 wt%, the obtained particles showed distinguished smaller size. Compared with solid lipid nanoparticles (SLN), NLC presented improved drug loading capacity which increased with increasing the liquid lipid content. The differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis indicated that the incorporation of liquid lipids could interfere with the crystallization of solid lipids. The drug in vitro release behavior from NLC displayed a biphasic drug release pattern with burst release at the initial stage and prolonged release afterwards, and the successful controlled release rate can be achieved by controlling the liquid lipid content.


Subject(s)
Drug Carriers/chemistry , Lipids/chemistry , Nanoparticles/chemistry , Silymarin/administration & dosage , Calorimetry, Differential Scanning , Drug Compounding , Microscopy, Electron, Transmission , Molecular Structure , Particle Size , Silybin , Silymarin/chemistry , Solubility , Stearates/chemistry , Surface Properties , Triglycerides/chemistry , X-Ray Diffraction
6.
Article in Chinese | MEDLINE | ID: mdl-19538834

ABSTRACT

OBJECTIVE: To study which classification model was most suitable for establishing a multi-tumor markers lung cancer prediction model, through established logistic regression model, decision trees model and artificial neural network model. METHODS: RIA analysis, ELISA, spectrophotometry, high-performance liquid chromatography (HPLC) and atomic absorption spectrometry were used to measure the serum CEA, CA125, gastrin, NSE, beta2-MG, Sil-6 receptors, sialic acid, nitric oxide, Cu, Zn, Ca and the pseudo-urine nucleoside of urine samples in lung cancer patients, benign lung disease patients and healthy controls. The lung cancer diagnosis models were established by logistic regression analysis, decision tree analysis and artificial neural network training. RESULTS: The diagnosis sensitivities of the logistic regression analysis, decision tree analysis and artificial neural network model with 12 tumor markers in lung cancer were 94.00%, 100.00% and 100.00%; the specificity were 100.00%, 98.89% and 100.00%; the total accurate 94.29%, 95.00% and 90.00%, respectively. CONCLUSION: The results of three classification models with 12 tumor markers in diagnosis of lung cancer are ideal. Especially the C5.0 decision tree model and the artificial neural network model are more suitable for the prediction and diagnosis of the lung cancer.


Subject(s)
Decision Trees , Logistic Models , Lung Neoplasms/diagnosis , Neural Networks, Computer , Aged , Biomarkers, Tumor/analysis , Female , Humans , Male , Middle Aged
7.
IUBMB Life ; 60(3): 185-94, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18380011

ABSTRACT

Recently, animal fatty acid synthase (FASN) is reported as a potential therapeutic target for obesity and cancer. Considerable interest has been developed in searching for novel inhibitors of this enzyme. An extract from Pangdahai has been found to inhibit FASN in both reversible and irreversible manners, with an IC(50) of 3.5 microg/ml and an apparent inactivation rate constant of k(obs) of 2.2 x 10(-3)/min. The kinetic study showed that the Pangdahai extract inhibited the overall FASN reaction uncompetitively with acetyl-CoA, but it presented in a mixed manner both with NADPH and with malonyl-CoA. Its major reacting site on this enzyme, as compared between two IC(50) values, is not in the beta-ketoacyl reduction domain. A weight reducing experiment in rats showed that the extract significantly reduced the adipose and food intake, but in view of statistics (P < 0.05), a correlation between the reductions in the adipose and in the food consumption and the inhibition of hepatic FASN could not be established. Three known flavonoid compounds were isolated from the extract and the structure-activity relationship was discussed.


Subject(s)
Drugs, Chinese Herbal/metabolism , Enzyme Inhibitors/pharmacology , Fatty Acid Synthases/antagonists & inhibitors , Flavonoids/pharmacology , Animals , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Ethanol/chemistry , Fatty Acid Synthases/metabolism , Flavonoids/chemistry , Flavonoids/metabolism , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Medicine, Chinese Traditional , Molecular Structure , Neoplasms/drug therapy , Obesity/drug therapy , Phytotherapy , Plant Extracts/chemistry , Plant Extracts/metabolism , Plant Extracts/pharmacology , Rats , Rats, Wistar , Sterculia/chemistry , Weight Loss
8.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 37(5): 754-6, 793, 2006 Sep.
Article in Chinese | MEDLINE | ID: mdl-17037744

ABSTRACT

OBJECTIVE: To explore the TGF-beta1, PDGF, CTGF serum expression significance in the occurrence and development of pneumoconiosis. METHODS: The serum levels of TGF-beta1, PDGF, CTGF in 70 patients with pneumoconiosis (including 29 patients with silicosis and 41 patients with coal pneumoconiosis) and 77 healthy individuals were detected by means of enzyme linked immunosorbent assay (ELISA). RESULTS: The serum levels of TGF-beta1, PDGF, CTGF in patients with pneumoconiosis were (44.95 +/- 23.72) ng/mL, (56.95 +/- 55.68) ng/mL, (346.70 +/- 259.49) pg/mL, the serum levels of control group were (6.81 +/- 4.99) ng/mL, (30.96 +/- 21.63) ng/mL, (307.49 +/- 235.40) pg/mL. There were significantly statistical differences between the case group and the control group in the serum levels of TGF-beta1 and PDGF (P < 0.05). There was no significantly statistical difference between the two groups in the serum levels of CTGF (P > 0.05). The serum levels of TGF-beta1 and PDGF in the patients with silicosis were higher than those in the patients with coal pneumoconiosis, and there was significantly statistical difference between the two groups (P < 0.05). The serum levels of TGF-beta1 and PDGF in the patients with pneumoconiosis decreased with the pneumoconiosis stage going up (P < 0.05). There was the bivariate correlation not only between the serum levels of TGF-beta1 and PDGF in the whole objects but also the serum levels of CTGF and PDGF (P < 0.05). CONCLUSIONS: The serum levels of TGF-beta1, PDGF, CTGF in the patients with pneumoconiosis may correlate with the pathological stages, styles and degree of pneumoconiosis.


Subject(s)
Immediate-Early Proteins/blood , Intercellular Signaling Peptides and Proteins/blood , Platelet-Derived Growth Factor/metabolism , Pneumoconiosis/blood , Transforming Growth Factor beta1/blood , Aged , Coal , Connective Tissue Growth Factor , Humans , Male , Middle Aged , Mining , Silicosis/blood
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