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1.
Toxicol Appl Pharmacol ; 300: 55-69, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27049118

RESUMO

14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Diterpenos/farmacologia , Estresse do Retículo Endoplasmático/fisiologia , Fator de Transcrição CHOP/biossíntese , Autofagia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Membranas Mitocondriais/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Regulação para Cima
2.
Int J Toxicol ; 34(5): 454-68, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26268769

RESUMO

A cell-based assay to measure cytochrome P450 3A4 (CYP3A4) induction was developed to screen for potential CYP3A4 inducers. This 96-well format assay utilizes HepG2 cells transfected with a gene construct of CYP3A4 proximal promoter linked to green fluorescence protein (GFP) gene, and the expression of the GFP is then measured quantitatively. Bergamottin at 5 to 25 µmol/L produced low induction relative to the positive control. Both curcumin and lycopene were not found to affect the expression of GFP, suggesting no induction properties toward CYP3A4. Interestingly, resveratrol produced significant induction from 25 µmol/L onward, which was similar to omeprazole and may warrant further studies. In conclusion, the present study demonstrated that this cell-based assay can be used as a tool to evaluate the potential CYP3A4 induction properties of compounds. However, molecular docking data have not provided satisfactory pointers to differentiate between CYP3A4 inducers from noninducers or from inhibitors, more comprehensive molecular screening may be indicated.


Assuntos
Bioensaio , Citocromo P-450 CYP3A/biossíntese , Indutores das Enzimas do Citocromo P-450/farmacologia , Citocromo P-450 CYP3A/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células Hep G2 , Humanos , Laboratórios , Simulação de Acoplamento Molecular , Regiões Promotoras Genéticas
3.
Planta Med ; 77(16): 1782-7, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21614753

RESUMO

Development of early stage atherosclerosis involves the activation of endothelial cells by oxidized low-density lipoprotein (oxLDL) with subsequent increases in endothelial permeability and expression of adhesion molecules favoring the adherence of monocytes to the endothelium. Cryptotanshinone (CTS), a major compound derived from the Chinese herb Salvia miltiorrhiza, is known for its protective effects against cardiovascular diseases. The aim of this study was to determine whether CTS could prevent the oxLDL-induced early atherosclerotic events. OxLDL (100 µg/mL) was used to increase endothelial permeability and induce monocyte-endothelial cell adhesion in human umbilical vein endothelial cells (HUVECs). Endothelial nitric oxide (NO) concentrations, a permeability-regulating molecule, and expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured. Results show that a) endothelial hyperpermeability was suppressed by 94 % (p < 0.005), b) monocyte adhesion by 105 % (p < 0.01), and c) ICAM-1 and VCAM-1 expressions by 90 % (p < 0.01) and 150 % (p < 0.005), respectively, when CTS was applied. In contrast, CTS increased NO levels by 129 % (p < 0.01) and was found to be noncytotoxic in the concentrations between 1-10 µM. These findings indicate that CTS suppresses an increase in endothelial permeability, likely due to the restoration of NO bioavailability in endothelial cells. They also indicate that CTS may attenuate monocyte adhesion to endothelial cells through the inhibition of adhesion molecules' expression. Thus, CTS may play an important role in the prevention of early or pre-lesional stage of atherosclerosis.


Assuntos
Aterosclerose/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , Fenantrenos/farmacologia , Salvia miltiorrhiza/química , Aterosclerose/induzido quimicamente , Disponibilidade Biológica , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Molécula 1 de Adesão Intercelular/efeitos dos fármacos , Molécula 1 de Adesão Intercelular/metabolismo , Lipoproteínas LDL/toxicidade , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Óxido Nítrico/farmacocinética , Permeabilidade/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacos , Molécula 1 de Adesão de Célula Vascular/metabolismo
4.
Data Brief ; 7: 1506-10, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27182548

RESUMO

The data presented in this article are related to the research article entitled "14-deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells", which the mechanistic toxicology properties of 14-deoxy-11,12-didehydroandrographolide (14-DDA) were investigated (Tan et al., 2016 [1]). This article describes the derivation of cytotoxic parameters of 14-DDA, cell viability data after double transfection and DDIT3 silencing in T-47D cells.

5.
Asian Pac J Cancer Prev ; 15(16): 6463-75, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25169472

RESUMO

The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.


Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Fitoterapia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Ciclo Celular , Proliferação de Células , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Complexos Multiproteicos/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Compostos Fitoquímicos/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
6.
Food Chem Toxicol ; 50(2): 431-44, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22101062

RESUMO

14-Deoxy-11,12-didehydroandrographolide is one of the principle compounds of the medicinal plant, Andrographis paniculata Nees. This study explored the mechanisms of 14-deoxy-11,12-didehydroandrographolide-induced toxicity and non-apoptotic cell death in T-47D breast carcinoma cells. Gene expression analysis revealed that 14-deoxy-11,12-didehydroandrographolide exerted its cytotoxic effects by regulating genes that inhibit the cell cycle or promote cell cycle arrest. This compound regulated genes that are known to reduce/inhibit cell proliferation, induce growth arrest and suppress cell growth. The growth suppression activities of this compound were demonstrated by a downregulation of several genes normally found to be over-expressed in cancers. Microscopic analysis revealed positive monodansylcadaverine (MDC) staining at 8h, indicating possible autophagosomes. TEM analysis revealed that the treated cells were highly vacuolated, thereby suggesting that 14-deoxy-11,12-didehydroandrographolide may cause autophagic morphology in these cells. This morphology may be correlated with the concurrent expression of genes known to affect lysosomal activity, ion transport, protein degradation and vesicle transport. Interestingly, some apoptotic-like bodies were found, and these bodies contained multiple large vacuoles, suggesting that this compound is capable of eliciting a combination of apoptotic and autophagic-like morphological characteristics.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Diterpenos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Estrutura Molecular , Reação em Cadeia da Polimerase em Tempo Real
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