RESUMEN
Multidrug resistance (MDR) mechanisms in cancer cells are greatly influenced by glutathione transferase P1-1 (hGSTP1-1). The use of synthetic or natural compounds as hGSTP1-1 inhibitors is considered an effective approach to overcome MDR. Nine compounds consisting of coumarin-6-sulfonamide linked to chalcone derivatives were synthesized and evaluated for their ability to inhibit hGSTP1-1. Among the synthetic derivatives, compounds 5g, 5f, and 5a displayed the most potent inhibitory effect, with IC50 values of 12.2 ± 0.5 µΜ, 12.7 ± 0.7 and 16.3 ± 0.6, respectively. Kinetic inhibition analysis of the most potent molecule, 5g, showed that it behaves as a mixed-type inhibitor of the target enzyme. An in vitro cytotoxicity assessment of 5a, 5f, and 5g against the human prostate cancer cell lines DU-145 and PC3, as well as the breast cancer cell line MCF-7, demonstrated that compound 5g exhibited the most pronounced cytotoxic effect on all tested cell lines. Molecular docking studies were performed to predict the structural and molecular determinants of 5g, 5f, and 5a binding to hGSTP1-1. In agreement with the experimental data, the results revealed that 5g exhibited the lowest docking score among the three studied inhibitors as a consequence of shape complementarity, governed by van der Waals, hydrogen bonds and a π-π stacking interaction. These findings suggest that coumarin-chalcone hybrids offer new perspectives for the development of safe and efficient natural product-based sensitizers that can target hGSTP1-1 for anticancer purposes.
Asunto(s)
Cumarinas , Gutatión-S-Transferasa pi , Simulación del Acoplamiento Molecular , Sulfonamidas , Humanos , Cumarinas/química , Cumarinas/farmacología , Gutatión-S-Transferasa pi/antagonistas & inhibidores , Gutatión-S-Transferasa pi/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacología , Línea Celular Tumoral , Chalcona/química , Chalcona/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Chalconas/química , Chalconas/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Células MCF-7RESUMEN
BACKGROUND: Glutathione S-Transferase (GST) is a family of phase II metabolizing enzymes contribute to detoxification and elimination of variety of endogenous as well as exogenous xenobiotics including chemotherapeutic agents. The comprehensive knowledge on the impact of genetic polymorphisms in GST) enzyme coding gene will help to understand the clinical outcomes in breast cancer patients treated with either Adriamycin or paclitaxel or combination of both. In this study we attempted to assess the genetic polymorphisms in GSTM1, GSTT1, GSTP1 and their association with Adriamycin and Paclitaxel induced toxicity reactions in breast cancer patients. METHODS: Two hundred BC patients receiving Adriamycin and Paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms in GSTM1, GSTP1 and GSTT1 gene were studied by PCR and RFLP analysis. RESULTS: After the univariate analysis of the genetic polymorphisms of GSTM1, GSTP1 and GSTT1 showed that GSTT1 null genotype showed significant association with neutropenia (OR=2.84, 95% CI: 1.06-7.56; p=0.036) in breast cancer patients treated with Adriamycin and GSTT1 null genotype in patients with >1 CINV toxicity confirmed significant correlation (OR=3.75, 95% CI: 1.46-9.59; p=0.005). The genetic polymorphisms of GSTP1 (exon 5) A/G heterozygous genotype was significant in grade >1 toxicity reactions of mucositis (OR=3.22, 95% CI: 1.06-9.71; p=0.037) in breast cancer patients administered with Paclitaxel chemotherapy. CONCLUSION: The findings obtained from this study proposed significant involvement of GSTT1-null genotype in hematological neutropenia toxicity in response to Adriamycin and GSTM1-null genotype showed negative association with non-hematological toxicity (bodyache) in response to Paclitaxel.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Doxorrubicina , Gutatión-S-Transferasa pi , Glutatión Transferasa , Paclitaxel , Polimorfismo Genético , Humanos , Glutatión Transferasa/genética , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Gutatión-S-Transferasa pi/genética , Paclitaxel/efectos adversos , Doxorrubicina/efectos adversos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Pronóstico , Genotipo , Anciano , Estudios de Seguimiento , Neutropenia/inducido químicamente , Neutropenia/genéticaRESUMEN
Hypertension is a leading risk factor for disease burden worldwide. Vascular contraction and remodeling contribute to the development of hypertension. Glutathione S-transferase P1 (Gstp1) plays several critical roles in both normal and neoplastic cells. In this study, we investigated the effect of Gstp1 on hypertension as well as on vascular smooth muscle cell (VSMC) contraction and phenotypic switching. We identified the higher level of Gstp1 in arteries and VSMCs from hypertensive rats compared with normotensive rats for the first time. We then developed Adeno-associated virus 9 (AAV9) mediated Gstp1 down-regulation and overexpression in rats and measured rat blood pressure by using the tail-cuff and the carotid catheter method. We found that the blood pressure of spontaneously hypertensive rats (SHR) rose significantly with Gstp1 down-regulation and reduced apparently after Gstp1 overexpression. Similar results were obtained from the observations of 2-kidney-1-clip renovascular (2K1C) hypertensive rats. Gstp1 did not influence blood pressure of normotensive Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Further in vitro study indicated that Gstp1 knockdown in SHR-VSMCs promoted cell proliferation, migration, dedifferentiation and contraction, while Gstp1 overexpression showed opposite effects. Results from bioinformatic analysis showed that the Apelin/APLNR system was involved in the effect of Gstp1 on SHR-VSMCs. The rise in blood pressure of SHR induced by Gstp1 knockdown could be reversed by APLNR antagonist F13A. We further found that Gstp1 enhanced the association between APLNR and Nedd4 E3 ubiquitin ligases to induce APLNR ubiquitination degradation. Thus, in the present study, we discovered a novel anti-hypertensive role of Gstp1 in hypertensive rats and provided the experimental basis for designing an effective anti-hypertensive therapeutic strategy.
Asunto(s)
Presión Sanguínea , Gutatión-S-Transferasa pi , Hipertensión , Músculo Liso Vascular , Ubiquitina-Proteína Ligasas Nedd4 , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Ubiquitinación , Animales , Masculino , Ratas , Proliferación Celular , Gutatión-S-Transferasa pi/metabolismo , Gutatión-S-Transferasa pi/genética , Hipertensión/metabolismo , Hipertensión/fisiopatología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/metabolismo , Ubiquitina-Proteína Ligasas Nedd4/genéticaRESUMEN
Glucocorticoids (GCs) are known to stimulate pancreatic beta (ß)-cell apoptosis via several mechanisms, including oxidative stress. Our previous study suggested an increase in dexamethasone-induced pancreatic ß-cell apoptosis via a reduction of glutathione S-transferase P1 (GSTP1), which is an antioxidant enzyme. Imatinib, which is a tyrosine kinase inhibitor, also exerts antioxidant effect. This study aims to test our hypothesis that imatinib would prevent pancreatic ß-cell apoptosis induced by dexamethasone via increased GSTP1 expression and reduced oxidative stress. Our results revealed that dexamethasone significantly increased apoptosis in INS-1 cells when compared to the control, and that imatinib significantly decreased INS-1 cell apoptosis induced by dexamethasone. Moreover, dexamethasone significantly increased superoxide production in INS-1 cells when compared to the control; however, imatinib, when combined with dexamethasone, significantly reduced superoxide production in INS-1 cells. Dexamethasone significantly decreased GSTP1, p-ERK1/2, and BCL2 protein expression, but significantly increased p-JNK, p-p38, and BAX protein expression in INS-1 cells-all compared to control. Importantly, imatinib significantly ameliorated the effect of dexamethasone on the expression of GSTP1, p-ERK1/2, p-JNK, p-p38 MAPK, BAX, and BCL2. Furthermore-6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX), which is a GSTP1 inhibitor, neutralized the protective effect of imatinib against pancreatic ß-cell apoptosis induced by dexamethasone. In conclusion, imatinib decreases pancreatic ß-cell apoptosis induced by dexamethasone via increased GSTP1 expression and reduced oxidative stress.
Asunto(s)
Apoptosis , Dexametasona , Gutatión-S-Transferasa pi , Mesilato de Imatinib , Células Secretoras de Insulina , Estrés Oxidativo , Mesilato de Imatinib/farmacología , Dexametasona/farmacología , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Gutatión-S-Transferasa pi/metabolismo , Animales , Ratas , Línea Celular , Superóxidos/metabolismoRESUMEN
Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases (GST) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1, GSTT1, GSTP1, and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association.
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Predisposición Genética a la Enfermedad , Gutatión-S-Transferasa pi , Glutatión Transferasa , Vasculitis por IgA , Polimorfismo de Nucleótido Simple , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios de Casos y Controles , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Vasculitis por IgA/genética , Inmunoglobulina A/sangre , Vasculitis/genéticaRESUMEN
The allele and genotype frequencies of the polymorphic loci CYP1A1 (rs1048943), GSTP1 (rs1695 and rs1138272), GSTM1, and GSTT1 genes were studied in 517 men: in 389 accumulated mercury pollution liquidators (207 firefighters of the Ministry of the Russian Federation for Civil Defence, Emergencies and Elimination of Consequences of Natural Disasters and 182 employees of the Federal Environmental Operator) and 128 former workers (82 patients in the delayed period of chronic mercury intoxication and 46 individuals contacted with mercury and had no chronic mercury intoxication). We found differences in the frequencies of AA and AG genotypes in groups of former workers (χ2=6.96, p=0.008) for the polymorphic locus rs1048943, while the AG-CYP1A1 genotype was characterized by a 5.5-fold decrease in the odds ratio for the development of chronic mercury intoxication (OR=0.18, p=0.0041). An unfavorable combination of genotypes of the studied polymorphic loci increases the risk of undesirable health effects.
Asunto(s)
Citocromo P-450 CYP1A1 , Glutatión Transferasa , Mercurio , Exposición Profesional , Xenobióticos , Humanos , Masculino , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Mercurio/toxicidad , Exposición Profesional/efectos adversos , Adulto , Xenobióticos/metabolismo , Citocromo P-450 CYP1A1/genética , Gutatión-S-Transferasa pi/genética , Persona de Mediana Edad , Intoxicación por Mercurio/genética , Frecuencia de los Genes/genética , Biotransformación/genética , Genotipo , Polimorfismo de Nucleótido Simple/genética , Federación de Rusia , Bomberos , AlelosRESUMEN
The oncogene and drug metabolism enzyme glutathione S-transferase P (GSTP) is also a GSH-dependent chaperone of signal transduction and transcriptional proteins with key role in liver carcinogenesis. In this study, we explored this role of GSTP in hepatocellular carcinoma (HCC) investigating the possible interaction of this protein with one of its transcription factor and metronome of the cancer cell redox, namely the nuclear factor erythroid 2-related factor 2 (Nrf2). Expression, cellular distribution, and function as glutathionylation factor of GSTP1-1 isoform were investigated in the mouse model of N-nitrosodiethylamine (DEN)-induced HCC and in vitro in human HCC cell lines. The physical and functional interaction of GSTP protein with Nrf2 and Keap1 were investigated by immunoprecipitation and gene manipulation experiments. GSTP protein increased its liver expression, enzymatic activity and nuclear levels during DEN-induced tumor development in mice; protein glutathionylation (PSSG) was increased in the tumor masses. Higher levels and a preferential nuclear localization of GSTP protein were also observed in HepG2 and Huh-7 hepatocarcinoma cells compared to HepaRG non-cancerous cells, along with increased basal and Ebselen-stimulated levels of free GSH and PSSG. GSTP activity inhibition with the GSH analogue EZT induced apoptotic cell death in HCC cells. Hepatic Nrf2 and c-Jun, two transcription factors involved in GSTP expression and GSH biosynthesis, were induced in DEN-HCC compared to control animals; the Nrf2 inhibitory proteins Keap1 and ß-TrCP also increased and oligomeric forms of GSTP co-immunoprecipitated with both Nrf2 and Keap1. Nrf2 nuclear translocation and ß-TrCP expression also increased in HCC cells, and GSTP transfection in HepaRG cells induced Nrf2 activation. In conclusion, GSTP expression and subcellular distribution are modified in HCC cells and apparently contribute to the GSH-dependent reprogramming of the cellular redox in this type of cancer directly influencing the transcriptional system Nrf2/Keap1.
Asunto(s)
Carcinoma Hepatocelular , Gutatión-S-Transferasa pi , Proteína 1 Asociada A ECH Tipo Kelch , Neoplasias Hepáticas , Factor 2 Relacionado con NF-E2 , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Animales , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Gutatión-S-Transferasa pi/metabolismo , Gutatión-S-Transferasa pi/genética , Masculino , Línea Celular Tumoral , Células Hep G2 , Glutatión/metabolismoRESUMEN
Although chlorambucil (CHL) is a long-established anticancer drug, the drug failure of CHL, mediated by the intracellular defense system consisting of glutathione (GSH) and GSH S-transferase pi (GST-pi), has significantly limited the application of CHL. To overcome this issue, we first designed a GSH-responsive small-molecule prodrug (EA-SS-CHL) by combining CHL and ethacrynic acid (EA). Subsequently, drug-loaded nanoparticles (ECPP) were formed by the self-assembly between EA-SS-CHL and amphiphilic PEG-PDLLA to improve the water solubility of the prodrug and its ability to target tumor sites. Upon exposure to high intracellular GSH concentration, EA-SS-CHL gradually degrades, leading to the release of EA and CHL. The presence of EA facilitates the depletion of GSH and inhibition of GST-pi, ultimately attenuating the detoxification of the intracellular defense system to CHL. Cytotoxicity studies and apoptosis assays demonstrate that ECPP exhibits higher therapeutic efficiency than CHL. Additionally,in vivotumor suppression effects and biocompatibility provide further evidence for the superiority of ECPP. This work presents a promising strategy to enhance the efficacy of CHL in cancer therapy.
Asunto(s)
Clorambucilo , Ácido Etacrínico , Glutatión , Micelas , Profármacos , Clorambucilo/farmacología , Clorambucilo/química , Profármacos/farmacología , Profármacos/química , Glutatión/metabolismo , Humanos , Animales , Ácido Etacrínico/farmacología , Ácido Etacrínico/química , Nanopartículas/química , Ratones , Gutatión-S-Transferasa pi/metabolismo , Gutatión-S-Transferasa pi/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Polietilenglicoles/química , Glutatión Transferasa/metabolismo , Portadores de Fármacos/química , Liberación de FármacosRESUMEN
BACKGROUND: Cardiovascular disease is one of the main causes of global mortality, and there is an urgent need for effective treatment strategies. Gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) promotes the development of cardiovascular diseases, and shizukaol C, a natural sesquiterpene isolated from Chloranthus multistachys with various biological activities, might exhibit beneficial role in preventing TMAO-induced vascular inflammation. PURPOSE: The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of shizukaol C on TMAO-induced vascular inflammation. METHODS: The effect and underlying mechanism of shizukaol C on TMAO-induced adhesion molecules expression, bone marrow-derived macrophages (BMDM) adhesion to VSMC were evaluated by western blot, cell adhesion assay, co-immunoprecipitation, immunofluorescence assay, and quantitative Real-Time PCR, respectively. To verify the role of shizukaol C in vivo, TMAO-induced vascular inflammation model were established using guidewire-induced injury on mice carotid artery. Changes in the intima area and the expression of GSTpi, VCAM-1, CD68 were examined using haematoxylin-eosin staining, and immunofluorescence assay. RESULTS: Our data demonstrated that shizukaol C significantly suppressed TMAO-induced adhesion molecule expression and the bone marrow-derived macrophages (BMDM) adhesion in vascular smooth muscle cells (VSMC). Mechanically, shizukaol C inhibited TMAO-induced c-Jun N-terminal kinase (JNK)-nuclear factor-kappa B (NF-κB)/p65 activation, and the JNK inhibition was dependent on the shizukaol C-mediated glutathione-S-transferase pi (GSTpi) expression. By further molecular docking and protein-binding analysis, we demonstrated that shizukaol C directly binds to Keap1 to induce Nrf2 nuclear translocation and upregulated GSTpi expression. Consistently, our in vivo experiment showed that shizukaol C elevated the expression level of GSTpi in carotid arteries and alleviates TMAO-induced vascular inflammation. CONCLUSION: Shizukaol C exerts anti-inflammatory effects in TMAO-treated VSMC by targeting Keap1 and activating Nrf2-GSTpi signaling and resultantly inhibits the downstream JNK-NF-κB/p65 activation and VSMC adhesion, and alleviates TMAO-induced vascular inflammation in vivo, suggesting that shizukaol C may be a potential drug for treating TMAO-induced vascular diseases.
Asunto(s)
Inflamación , Músculo Liso Vascular , Sesquiterpenos , Animales , Masculino , Ratones , Antiinflamatorios/farmacología , Adhesión Celular/efectos de los fármacos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Proteína 1 Asociada A ECH Tipo Kelch/efectos de los fármacos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Metilaminas/farmacología , Ratones Endogámicos C57BL , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Sesquiterpenos/farmacología , Transducción de Señal/efectos de los fármacos , Gutatión-S-Transferasa pi/efectos de los fármacos , Gutatión-S-Transferasa pi/metabolismoRESUMEN
In the department of Boyacá, Colombia, agriculture stands as one of the primary economic activities. However, the escalating utilization of pesticides within this sector has sparked concern regarding its potential correlation with elevated risks of genotoxicity, chromosomal alterations, and carcinogenesis. Furthermore, pesticides have been associated with a broad spectrum of genetic polymorphisms that impact pivotal genes involved in pesticide metabolism and DNA repair, among other processes. Nonetheless, our understanding of the genotoxic effects of pesticides on the chromosomes (as biomarkers of effect) in exposed farmers and the impact of genetic polymorphisms (as susceptibility biomarkers) on the increased risk of chromosomal damage is still limited. The aim of our study was to evaluate chromosomal alterations, chromosomal instability, and clonal heterogeneity, as well as the presence of polymorphic variants in the GSTP1 and XRCC1 genes, in peripheral blood samples of farmers occupationally exposed to pesticides in Aquitania, Colombia, and in an unexposed control group. Our results showed statistically significant differences in the frequency of numerical chromosomal alterations, chromosomal instability, and clonal heterogeneity levels between the exposed and unexposed groups. In addition, we also found a higher frequency of chromosomal instability and clonal heterogeneity in exposed individuals carrying the heterozygous GSTP1 AG and XRCC1 (exon 10) GA genotypes. The evaluation of chromosomal alterations and chromosomal instability resulting from pesticide exposure, combined with the identification of polymorphic variants in the GSTP1 and XRCC1 genes, and further research involving a larger group of individuals exposed to pesticides could enable the identification of effect and susceptibility biomarkers. Such markers could prove valuable for monitoring individuals occupationally exposed to pesticides.
Asunto(s)
Inestabilidad Cromosómica , Agricultores , Gutatión-S-Transferasa pi , Exposición Profesional , Plaguicidas , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X , Humanos , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genética , Gutatión-S-Transferasa pi/genética , Plaguicidas/toxicidad , Plaguicidas/efectos adversos , Exposición Profesional/efectos adversos , Masculino , Inestabilidad Cromosómica/efectos de los fármacos , Adulto , Persona de Mediana Edad , Femenino , Biomarcadores , Aberraciones Cromosómicas/inducido químicamente , Colombia , Polimorfismo de Nucleótido Simple , Predisposición Genética a la EnfermedadRESUMEN
Background and Objectives: Despite improvements in screening programs, a large number of patients with colorectal cancer (CRC) are diagnosed in an advanced disease stage. Previous investigations imply that glutathione transferases (GSTs) might be associated with the development and progression of CRC. Moreover, the detoxification mechanism of oxaliplatin, which represents the first line of treatment for advanced CRC, is mediated via certain GSTs. The aim of this study was to evaluate the significance of certain GST genetic variants on CRC prognosis and the efficacy of oxaliplatin-based treatment. Materials and Methods: This prospective study included 523 patients diagnosed with CRC in the period between 2014 and 2016, at the Digestive Surgery Clinic, University Clinical Center of Serbia, Belgrade. Patients were followed for a median of 43.47 ± 17.01 months (minimum 1-63 months). Additionally, 109 patients with advanced disease, after surgical treatment, received FOLFOX6 treatment as a first-line therapy between 2014 and 2020. The Kaplan-Meier method was used to analyze cumulative survival, and the Cox proportional hazard regression model was used to study the effects of different GST genotypes on overall survival. Results: Individuals with the GSTM1-null genotype and the GSTP1 IleVal+ValVal (variant) genotype had significantly shorter survival when compared to referent genotypes (GSTM1-active and GSTP1 IleIle) (log-rank: p = 0.001). Moreover, individuals with the GSTM1-null genotype who received 5-FU-based treatment had statistically significantly shorter survival when compared to individuals with the GSTM1-active genotype (log-rank: p = 0.05). Conclusions: Both GSTM1-null and GSTP1 IleVal+ValVal (variant) genotypes are associated with significantly shorter survival in CRC patients. What is more, the GSTM1-null genotype is associated with shorter survival in patients receiving FOLOFOX6 treatment.
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Adenocarcinoma , Neoplasias Colorrectales , Gutatión-S-Transferasa pi , Glutatión Transferasa , Polimorfismo Genético , Humanos , Gutatión-S-Transferasa pi/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/tratamiento farmacológico , Glutatión Transferasa/genética , Femenino , Masculino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Serbia , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Genotipo , Pronóstico , Estimación de Kaplan-Meier , Compuestos Organoplatinos/uso terapéutico , Leucovorina/uso terapéutico , Oxaliplatino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Modelos de Riesgos Proporcionales , AdultoRESUMEN
Individuals working in diverse fields are consistently exposed to work-related pollutants that can impact their overall health. The current study investigated the presence of pollutants in seven different occupational groups and their impact on human health. Biochemical and genetic approaches were employed. Heavy metals were determined by ICP-MS technique. Oxidative stress biochemical markers and molecular analysis of the glutathione transferases gene SNPs (GSTT1, GSTM1, GSTP1), catalase (CAT, rs7943316), and superoxide dismutase (SOD, rs17880487) was carried out. The results revealed a significantly higher quantity of Cd among five occupational groups. Catalase, malonaldehyde, and glutathione was significantly dysregulated. Molecular analysis of the gene SNPs suggests a probable relationship between the antioxidants and the phenotypic expression of the CAT, GSTP1, GSTT1, and GSTM1 SNPs. It is concluded that chronic exposure to occupational contaminants like Cd affects human health through oxidative stress in association with some of their gene SNPs.
Asunto(s)
Catalasa , Gutatión-S-Transferasa pi , Glutatión Transferasa , Metales Pesados , Exposición Profesional , Estrés Oxidativo , Polimorfismo de Nucleótido Simple , Superóxido Dismutasa , Humanos , Glutatión Transferasa/genética , Catalasa/genética , Gutatión-S-Transferasa pi/genética , Metales Pesados/toxicidad , Superóxido Dismutasa/genética , Adulto , Masculino , Antioxidantes/metabolismo , Malondialdehído , Glutatión/metabolismoRESUMEN
We investigated possible associations between the internal concentrations of POPs and correlations between blood and tumor tissue concentrations in patients who underwent surgery for breast cancer and breast reduction as controls. Genetic variations in CYP1A1, GSTP1, GSTM1, and GSTT1 and hOGG1 were evaluated to determine whether they represent risk factors for breast cancer. Certain POPs have been found to be associated with breast cancer development. GST-P1 polymorphism represented a significant risk for breast cancer with unadjusted OR. However, the GSTT1 null polymorphism represented a significant risk for breast cancer when OR adjusted for age and smoking status. CYP1A1 polymorphism was a significant risk factor for breast cancer, regardless of whether the OR was adjusted. These results suggest that exposure to certain POPs, GSTT1 and CYP1A1 polymorphisms, age, and smoking status are risk factors for breast cancer. In addition, the blood concentrations of some POPs represent surrogates for breast tissue concentrations.
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Neoplasias de la Mama , Citocromo P-450 CYP1A1 , Predisposición Genética a la Enfermedad , Glutatión Transferasa , Contaminantes Orgánicos Persistentes , Humanos , Neoplasias de la Mama/genética , Femenino , Glutatión Transferasa/genética , Citocromo P-450 CYP1A1/genética , Persona de Mediana Edad , Adulto , Contaminantes Orgánicos Persistentes/sangre , Polimorfismo Genético , Anciano , Gutatión-S-Transferasa pi/genética , Factores de Riesgo , ADN GlicosilasasRESUMEN
BACKGROUND: This meta-analysis aimed to systematically summarize the association between cancer risks and glutathione s-transferases (GSTs) among smokers and drinkers. METHODS: Literature was searched through PubMed, Web of Science, CNKI, and WANFANG published from 2001 to 2022. Stata was used with fixed-effect model or random-effect model to calculate pooled odds ratios (ORs) and the 95% confidence interval (95% CI). Sensitivity and heterogeneity calculations were performed, and publication bias was analyzed by Begg and Egger's test. Regression analysis was performed on the correlated variables about heterogeneity, and the false-positive report probabilities (FPRP) and the Bayesian False Discovery Probability (BFDP) were calculated to assess the confidence of a statistically significant association. RESULTS: A total of 85 studies were eligible for GSTs and cancer with smoking status (19,604 cases and 23,710 controls), including 14 articles referring to drinking status (4409 cases and 5645 controls). GSTM1-null had significant associations with cancer risks (for smokers: ORâ =â 1.347, 95% CI: 1.196-1.516, Pâ <â .001; for nonsmokers: ORâ =â 1.423, 95% CI: 1.270-1.594, Pâ <â .001; for drinkers: ORâ =â 1.748, 95% CI: 1.093-2.797, Pâ =â .02). GSTT1-null had significant associations with cancer risks (for smokers: ORâ =â 1.356, 95% CI: 1.114-1.651, Pâ =â .002; for nonsmokers: ORâ =â 1.103, 95% CI: 1.011-1.204, Pâ =â .028; for drinkers: ORâ =â 1.423, 95% CI: 1.042-1.942, Pâ =â .026; for nondrinkers: ORâ =â 1.458, 95% CI: 1.014-2.098, Pâ =â .042). Negative associations were found between GSTP1rs1695(AGâ +â GG/AA) and cancer risks among nondrinkers (ORâ =â 0.840, 95% CI: 0.711-0.985, Pâ =â .032). CONCLUSIONS: GSTM1-null and GSTT1-null might be related cancers in combination with smoking or drinking, and GSTP1rs1695 might be associated with cancers among drinkers.
Asunto(s)
Gutatión-S-Transferasa pi , Neoplasias , Humanos , Gutatión-S-Transferasa pi/genética , Teorema de Bayes , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Fumar/efectos adversos , Neoplasias/etiología , Neoplasias/genética , Glutatión , Factores de Riesgo , Genotipo , Estudios de Casos y ControlesRESUMEN
Olanzapine treatment sometimes produces transient liver biochemistry abnormalities, and such drug-induced liver injuries are mainly monitored by measuring blood levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), whereas alpha-glutathione-S-transferase (α-GST) is not routinely measured in clinics, even though it can serve as an earlier and more specific biomarker of liver damage. Susceptibility to drug-induced liver injury can much depend on the gene polymorphisms regulating the activity of DNA detoxification and repair enzymes. The aim of this study was to evaluate which of the three liver enzymes - α-GST, ALT, and AST - is the most sensitive biomarker of olanzapine-induced liver injury and how their blood levels are affected by the GSTT1, GSTM1, GSTP1, and OGG1 gene polymorphisms in 30 olanzapine-treated patients. Contrary to our hypothesis, the increase in serum α-GST levels was not significantly greater than that of the transaminases. ALT turned out to be an earlier biomarker of liver injury than the other two enzymes. No significant association was found between gene polymorphisms and liver enzyme levels, save for GSTP1 Ile/Val + Val/Val and ALT, which points to this genotype as a risk factor for drug-induced liver injury. Future studies might help to identify the underlying mechanisms of transient liver enzyme increase associated with this genotype.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Polimorfismo Genético , Humanos , Olanzapina , Glutatión Transferasa/genética , Gutatión-S-Transferasa pi/genética , Factores de Riesgo , Biomarcadores , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Estudios de Casos y Controles , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND AND OBJECTIVE: Several genetic variations are associated with acute myeloid leukemia (AML) susceptibility, including the GSTP1 Ile105Val polymorphism. Even with the existing meta-analysis conducted on the topic, no consensus has been reached since none of the studies available performed in-depth data analysis. Hence, we performed an updated systematic review and meta-analysis in this paper to obtain more precise estimates. MATERIALS AND METHODS: We searched various databases and calculated the odds ratio (OR) and 95% confidence interval (CI) to examine whether the GSTP1 Ile105Val polymorphism is associated with AML susceptibility. Further statistical analysis was also done to obtain more accurate and reliable findings. RESULTS: A total of 15 studies are included in the systematic review, but only 9 were included in the meta-analysis due to the studies deviating from the Hardy-Weinberg equilibrium. The analysis showed significantly increased susceptibility to AML in the allelic, co-dominant, and recessive models. Furthermore, subgroup analysis noted increased AML susceptibility in the non-Asian population. Comparing the proportions of the genotypes and alleles showed a significantly higher proportion of the Val/Val genotype and Val allele in the non-Asian cohort. CONCLUSION: The GSTP1 Ile105Val polymorphism is significantly associated with AML susceptibility, especially among non-Asians. Further investigation should be performed to strengthen the current results.
Asunto(s)
Predisposición Genética a la Enfermedad , Gutatión-S-Transferasa pi , Leucemia Mieloide Aguda , Humanos , Estudios de Casos y Controles , Genotipo , Gutatión-S-Transferasa pi/genética , Leucemia Mieloide Aguda/genética , Polimorfismo Genético , Polimorfismo de Nucleótido SimpleRESUMEN
Malignant tumors contribute significantly to human mortality. Chemotherapy is a commonly used treatment for tumors. However, due to the low selectivity of chemotherapeutic drugs, immune cells can be damaged during antitumor treatment, resulting in toxicity. Lipopolysaccharide (LPS) can stimulate immune cells to respond to foreign substances. Here, we found that 10â¯ng/mL LPS could induce tolerance to antitumor drugs in macrophages without altering the effect of the drugs on tumor cells. Differentially expressed genes (DEGs) were identified between cells before and after LPS administration using transcriptome sequencing and found to be mainly associated with ATP-binding cassette (ABC)-resistant transporters and glutathione S-transferase (GST). LPS was shown by qRT-PCR and western blotting to promote the expression of ABCC1, GSTT1, and GSTP1 by 38.3â¯%, 194.8â¯%, and 27.0â¯%. Furthermore, three inhibitors (inhibitors of GST, glutathione synthesis, and ABCC1) were used for further investigation, showing that these inhibitors reduced macrophage survival rates by 44.0â¯%, 52.3â¯%, and 43.3â¯%, while the intracellular adriamycin content increased by 28.9â¯%, 42.9â¯%, and 51.3â¯%, respectively. These findings suggest that the protective mechanism of LPS on macrophages is associated with increased GST activity, the consumption of glutathione, and increased expression of ABCC1 protein. Therefore, LPS has a potential role in enhancing immunity.
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Lipopolisacáridos , Macrófagos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Ratones , Animales , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Antineoplásicos/farmacología , Doxorrubicina/farmacología , Glutatión Transferasa/metabolismo , Glutatión Transferasa/genética , Células RAW 264.7 , Humanos , Glutatión/metabolismo , Gutatión-S-Transferasa pi/genética , Gutatión-S-Transferasa pi/metabolismo , Supervivencia Celular/efectos de los fármacosRESUMEN
PURPOSE: Majority of the gallbladder cancer (GBC) cases are diagnosed at an advanced stage where chemotherapy alone (or in combination with other treatment methods) is mainly opted as therapeutic approach. However, success or failure of this approach largely depends on the interindividual genetic differences. Careful consideration on the genetic association could assist in the evaluation of patient's treatment response and survival rate. Hence, the present study aims to investigate the survival of patients with GBC and their treatment response to gemcitabine and cisplatin/carboplatin-based chemotherapy in association with Glutathione S-transferase (GSTs) gene polymorphism. MATERIAL AND METHODS: A total of 216 histologically confirmed cases of gallbladder cancer were recruited. A total of 180 patients were treated with gemcitabine and cisplatin/carboplatin-based chemotherapy. GSTM1, GSTT1, and GSTP1 genotypes were determined by multiplex PCR and by PCR restriction fragment length polymorphism (PCR-RFLP), respectively. The influence of genetic polymorphism on overall survival was analyzed by Kaplan-Meier method, survival rate difference was analyzed by log-rank test, and hazard ratio for mortality outcomes was estimated using Cox regression method. RESULTS: GBC patients having genotype GSTP1 (AG + GG) showed poor 3-year survival rate of 0.8% compared to 10.9% of GSTP1 (AA) genotype (χ2 = 6.456, P = 0.011). The multivariate Cox regression results showed that the death risk was significantly higher in GSTP1 (AG + GG) genotype (HR = 3.858, P = 0.050). We found no association of GSTM1 and GSTT1 gene polymorphism with the survival; however, the combined genotypes of GSM1/GSTP1, GSTT1/GSTP1, and GSTM1/GSTT1/GSTP1 were associated with survival (P = 0.053, 0.006, and 0.058, respectively). Increased death hazard was noted by the genotype combinations of GSTM1+/GSTP1AG + GG (HR = 3.484, P = 0.024), GSTM1-/GSTP1AG + GG (HR = 2.721, P = 0.014), GSTT1+/GSTP1AG + GG (HR = 20.690, P = 0.001), and GSTT1-/GSTP1AA (HR = 26.111, P < 0.0001). Our findings indicate that chemotherapy treatment response of GSTP1 (AG + GG) has 1.62-fold increased risk for progression compared to GSTP1 (AA) genotype (p = 0.018); however, none of the genotypes showed association with overall survival and death risk after chemotherapeutic treatment. CONCLUSION: We found that the presence of GSTP1 (AG + GG) genotype showed survival disadvantage and poor treatment outcomes in response to gemcitabine and cisplatin/carboplatin-based chemotherapy. This could serve as biomarker, and future research in pharmacogenomics will definitely pave the way for the development of better treatment approach for GBC.
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Cisplatino , Neoplasias de la Vesícula Biliar , Humanos , Cisplatino/uso terapéutico , Carboplatino , Gemcitabina , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Neoplasias de la Vesícula Biliar/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Glutatión Transferasa/genética , Gutatión-S-Transferasa pi/genética , Genotipo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: Considering the inadequacy of PSA measurement in the diagnosis of prostate cancer, it is aimed to establish a potential liquid biopsy diagnostic panel. MATERIALS AND METHODS: 39 patients who underwent TRUS-biopsy and 15 healthy volunteers were included. Approximately 15 ml of venous blood samples taken from healthy volunteers and patients before biopsy were separated as plasma. Hypermethylation status of GSTP1 and RASSF1:RASSF2 genes was revealed in cfDNA materials collected from plasma samples. Correlation of this epigenetic change detected in PCa, BPH and healthy volunteer groups with pathology results was examined. RESULTS: Pathology reports of 39 patients included were 13 PCa, 3 ASAP, 3 HGPIN, and 20 BPH. In total, 3 of the patients with PCa had positive GSTP1, 4 had RASSF1 and 9 had positive RASSF2 methylation. It was seen that RASSF2 had the highest sensitivity (69%), specificity (39%) and NPV (80%), while RASSF1 had the highest PPV (30%). When the binary combinations of genes were examined it was observed that the GSTP1:RASSF1 combination had the highest sensitivity (46%), specificity (76%) and NPV (82%). When the methylation of all three genes was examined, it was observed that the sensitivity was quite low (8%), but the specificity (83%) increased significantly. CONCLUSION: Although we observed that the GSTP1 and RASSF1 methylation positivity rates that we examined in our study were higher in patients without prostate cancer, we found that the RASSF2 methylation rate was higher in patients with prostate cancer. randomized controlled studies are needed.
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Metilación de ADN , Gutatión-S-Transferasa pi , Neoplasias de la Próstata , Proteínas Supresoras de Tumor , Humanos , Masculino , Gutatión-S-Transferasa pi/genética , Gutatión-S-Transferasa pi/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/diagnóstico , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/sangre , Anciano , Persona de Mediana Edad , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: Low-dose ionizing radiation-induced protection and damage are of great significance among radiation workers. We aimed to study the role of glutathione S-transferase Pi (GSTP1) in low-dose ionizing radiation damage and clarify the impact of ionizing radiation on the biological activities of cells. RESULTS: In this study, we collected peripheral blood samples from healthy adults and workers engaged in radiation and radiotherapy and detected the expression of GSTP1 by qPCR. We utilized γ-rays emitted from uranium tailings as a radiation source, with a dose rate of 14 µGy/h. GM12878 cells subjected to this radiation for 7, 14, 21, and 28 days received total doses of 2.4, 4.7, 7.1, and 9.4â¯mGy, respectively. Subsequent analyses, including flow cytometry, MTS, and other assays, were performed to assess the ionizing radiation's effects on cellular biological functions. In peripheral blood samples collected from healthy adults and radiologic technologist working in a hospital, we observed a decreased expression of GSTP1 mRNA in radiation personnel compared to the healthy controls. In cultured GM12878 cells exposed to low-dose ionizing radiation from uranium tailings, we noted significant changes in cell morphology, suppression of proliferation, delay in cell cycle progression, and increased apoptosis. These effects were partially reversed by overexpression of GSTP1. Moreover, low-dose ionizing radiation increased GSTP1 gene methylation and downregulated GSTP1 expression. Furthermore, low-dose ionizing radiation affected the expression of GSTP1-related signaling molecules. CONCLUSIONS: This study shows that low-dose ionizing radiation damages GM12878 cells and affects their proliferation, cell cycle progression, and apoptosis. In addition, GSTP1 plays a modulating role under low-dose ionizing radiation damage conditions. Low-dose ionizing radiation affects the expression of Nrf2, JNK, and other signaling molecules through GSTP1.