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1.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451103

RESUMEN

Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including cyclin-D1, BCL2, FZD1, GINS-1, and MMP9. Further, computer-based analysis of the clones obtained from the DNA:CD44v6 complex revealed the presence of various consensus binding sites for core stemness-associated transcription factors "CTOS" (c-Myc, TWIST1, OCT4, and SOX2). Simultaneous expressions of CD44v6 and CTOS in CD44v6 knockout CICs reverted differentiated CD44v6-knockout CICs into CICs. Finally, this study for the first time describes a positive feedback loop that couples YB-1 induction and CD44 alternative splicing to sustain the MDR1 and CD44v6 expressions, and CD44v6 is required for the reversion of differentiated tumor cells into CICs.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Receptores de Hialuranos/genética , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Proteína 1 de Unión a la Caja Y/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Sistemas CRISPR-Cas , Diferenciación Celular , Autorrenovación de las Células/genética , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Resistencia a Antineoplásicos/genética , Fluorouracilo/uso terapéutico , Perfilación de la Expresión Génica , Técnicas de Inactivación de Genes , Humanos , Receptores de Hialuranos/metabolismo , Inmunofenotipificación , Leucovorina/uso terapéutico , Compuestos Organoplatinos/uso terapéutico , Transducción de Señal
2.
Mol Pharmacol ; 99(3): 184-196, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33483427

RESUMEN

The HIV protease inhibitor nelfinavir is currently being analyzed for repurposing as an anticancer drug for many different cancers because it exerts manifold off-target protein interactions, finally resulting in cancer cell death. Xenosensing pregnane X receptor (PXR), which also participates in the control of cancer cell proliferation and apoptosis, was previously shown to be activated by nelfinavir; however, the exact molecular mechanism is still unknown. The present study addresses the effects of nelfinavir and its major and pharmacologically active metabolite nelfinavir hydroxy-tert-butylamide (M8) on PXR to elucidate the underlying molecular mechanism. Molecular docking suggested direct binding to the PXR ligand-binding domain, which was confirmed experimentally by limited proteolytic digestion and competitive ligand-binding assays. Concentration-response analyses using cellular transactivation assays identified nelfinavir and M8 as partial agonists with EC50 values of 0.9 and 7.3 µM and competitive antagonists of rifampin-dependent induction with IC50 values of 7.5 and 25.3 µM, respectively. Antagonism exclusively resulted from binding into the PXR ligand-binding pocket. Impaired coactivator recruitment by nelfinavir as compared with the full agonist rifampin proved to be the underlying mechanism of both effects on PXR. Physiologic relevance of nelfinavir-dependent modulation of PXR activity was investigated in respectively treated primary human hepatocytes, which showed differential induction of PXR target genes and antagonism of rifampin-induced ABCB1 and CYP3A4 gene expression. In conclusion, we elucidate here the molecular mechanism of nelfinavir interaction with PXR. It is hypothesized that modulation of PXR activity may impact the anticancer effects of nelfinavir. SIGNIFICANCE STATEMENT: Nelfinavir, which is being investigated for repurposing as an anticancer medication, is shown here to directly bind to human pregnane X receptor (PXR) and thereby act as a partial agonist and competitive antagonist. Its major metabolite nelfinavir hydroxy-tert-butylamide exerts the same effects, which are based on impaired coactivator recruitment. Nelfinavir anticancer activity may involve modulation of PXR, which itself is discussed as a therapeutic target in cancer therapy and for the reversal of chemoresistance.


Asunto(s)
Hepatocitos/metabolismo , Nelfinavir/análogos & derivados , Nelfinavir/farmacología , Receptor X de Pregnano/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Sitios de Unión , Citocromo P-450 CYP3A/genética , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Humanos , Modelos Moleculares , Conformación Molecular , Simulación del Acoplamiento Molecular , Nelfinavir/química , Receptor X de Pregnano/agonistas , Receptor X de Pregnano/antagonistas & inhibidores , Receptor X de Pregnano/química , Cultivo Primario de Células
3.
Toxicol Lett ; 334: 87-93, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-33002526

RESUMEN

The interplays between the metabolic products of intestinal microbiota and the host signaling through xenobiotic receptors, including pregnane X receptor (PXR), are of growing interest, in the context of intestinal health and disease. A distinct class of microbial catabolites is formed from dietary tryptophan, having the indole scaffold in their core structure, which is a biologically active entity. In the current study, we examined a series of ten tryptophan microbial catabolites for their interactions with PXR signaling. Utilizing a reporter gene assay, we identified indole (IND) and indole-3-acetamide (IAD) as PXR agonists. IND and IAD induced PXR-regulated genes CYP3A4 and MDR1 in human intestinal cancer cells. Using time-resolved fluorescence resonance energy transfer, we show that IND (IC50 292 µM) and IAD (IC50 10 µM) are orthosteric ligands of PXR. Binding of PXR in its DNA response elements was enhanced by IND and IAD, as revealed by chromatin immunoprecipitation assay. We demonstrate that tryptophan microbial intestinal metabolites IND and IAD are ligands and agonists of human PXR. These findings are of particular importance in understanding the roles of microbial catabolites in human physiology and pathophysiology. Furthermore, these results are seminal in expanding potential drug repertoire through microbial metabolic mimicry.


Asunto(s)
Microbioma Gastrointestinal , Ácidos Indolacéticos/metabolismo , Indoles/metabolismo , Mucosa Intestinal , Receptor X de Pregnano/agonistas , Triptófano/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Línea Celular Tumoral , Células Cultivadas , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genes Reporteros , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Ligandos , Masculino , Receptor X de Pregnano/genética , Unión Proteica , Transfección
4.
J Med Life ; 13(3): 349-355, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33072207

RESUMEN

Chronic obstructive pulmonary disease is a multifactorial disease characterized by gene-gene interaction as well as environmental effects. The incidence of type 2 diabetes mellitus is proved to be higher in the presence of chronic obstructive pulmonary disease than in the case of its absence. We aimed to study the genotypes of MDR1 (C3435T) gene polymorphism and its relationship with clinical, instrumental, and laboratory parameters in chronic obstructive pulmonary disease associated with type 2 diabetes mellitus. All the patients were divided into two groups. The first group included 53 patients with chronic obstructive pulmonary disease, and the second group included 49 patients with chronic obstructive pulmonary disease with comorbid type 2 diabetes mellitus. The COPD assessment test (CAT), 6-minute walk test, BODE integral index, spirometry, and bioimpedansometry were used for examination. Lipid spectrum, carbohydrate metabolism, endothelial functional status, leptin, adiponectin, and serum levels were also determined by means of enzyme immunoassay. Our study results showed no significant difference between the genotypes of the control group of healthy individuals and patients with chronic obstructive pulmonary disease and comorbid type 2 diabetes mellitus. Though, a certain association of this gene polymorphism with clinical findings by CAT-test, specific parameters of carbohydrate (fasting glucose) and lipid metabolism (total cholesterol and low-density cholesterol lipoproteins), endothelial functional state (nitrate/nitrite level) with the minor allele T available was found.


Asunto(s)
Diabetes Mellitus Tipo 2/complicaciones , Polimorfismo de Nucleótido Simple/genética , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Proteína C-Reactiva/metabolismo , Metabolismo de los Hidratos de Carbono , Citocinas/metabolismo , Impedancia Eléctrica , Células Endoteliales/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Prueba de Paso
5.
Anticancer Res ; 40(9): 4921-4928, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32878780

RESUMEN

BACKGROUND/AIM: Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research. MATERIALS AND METHODS: Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay. RESULTS: Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 µM). Thioridazine was the most potent among the three phenothiazines. CONCLUSION: Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Compuestos de Organoselenio/farmacología , Fenotiazinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Ratones , Estructura Molecular , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/química , Fenotiazinas/síntesis química , Fenotiazinas/química
6.
Medicine (Baltimore) ; 99(36): e22084, 2020 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-32899083

RESUMEN

RATIONALE: Dabigatran is a direct thrombin inhibitor that is widely used to prevent the formation of thrombus formation. Amiodarone can increase the plasma concentration of dabigatran. CES1 (carboxylesterase 1) and ABCB1 (ATP-binding cassette subfamily B member 1) genetic polymorphisms associate with the pharmacokinetics of dabigatran. PATIENT CONCERNS: A 62-year-old woman was admitted to the hospital due to chest tightness, fatigue, and discomfort despite long-term anticoagulation with dabigatran 110 mg twice daily for 6 months, with concomitant use of amiodarone. DIAGNOSES: Left atrial appendage thrombus formation with a history of atrial fibrillation. INTERVENTIONS: The clinician changed dabigatran to warfarin. To explore the causes of insufficient anticoagulation using dabigatran in this patient, we examined the ABCB1 and CES1 genes. Results showed that she carried ABCB1 variant alleles with 3 heterozygote single nucleotide polymorphisms (SNPs: rs4148738, rs1045642, rs2032582) and CES1 variant alleles with 2 heterozygote SNPs (rs2244613, rs4580160). OUTCOMES: The left atrial appendage thrombus disappeared. LESSONS: Multiple mutations in the ABCB1 and CES1 genes may influence the pharmacokinetics of dabigatran and could have contributed to the thrombus formation in the left atrial appendage.


Asunto(s)
Apéndice Atrial/patología , Fibrilación Atrial/complicaciones , Hidrolasas de Éster Carboxílico/genética , Trombosis/etiología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antitrombinas/administración & dosificación , Antitrombinas/farmacocinética , Apéndice Atrial/diagnóstico por imagen , Dabigatrán/administración & dosificación , Dabigatrán/farmacocinética , Femenino , Humanos , Persona de Mediana Edad , Trombosis/prevención & control
7.
Eur J Drug Metab Pharmacokinet ; 45(6): 749-760, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32886348

RESUMEN

BACKGROUND AND OBJECTIVE: Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. METHODS: The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12 months post-transplantation. RESULTS: The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. CONCLUSION: The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.


Asunto(s)
Citocromo P-450 CYP3A/genética , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Trasplante de Riñón/métodos , Tacrolimus/farmacocinética , Tacrolimus/uso terapéutico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Femenino , Genotipo , Tasa de Filtración Glomerular , Supervivencia de Injerto , Humanos , Inmunosupresores/administración & dosificación , Isoenzimas/genética , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Estudios Retrospectivos , Tacrolimus/administración & dosificación
8.
Pharm Res ; 37(10): 194, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32918191

RESUMEN

PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). RESULTS: MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. CONCLUSION: cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/deficiencia , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Proteínas de Neoplasias/metabolismo , Farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Animales , Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células CACO-2 , Permeabilidad de la Membrana Celular , Dibenzocicloheptenos/farmacología , Dicetopiperazinas/farmacología , Perros , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Células de Riñón Canino Madin Darby , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Prazosina/farmacocinética , Quinidina/farmacocinética , Quinolinas/farmacología , Especificidad por Sustrato , Transfección
9.
Medicine (Baltimore) ; 99(35): e21704, 2020 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-32871888

RESUMEN

To explore the relationship between C3435T polymorphism of multi-drug resistance gene (MDR1) gene and susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of diffuse large B-cell lymphoma (DLBCL) in XinJiang.The peripheral venous blood samples of 54 patients with DLBCL and 60 healthy controls were collected. The alleles and genotypes of MDR1 gene C3435T were detected by DNA direct extraction with PCR technique, and the frequency of C3435T allele and genotypes were detected by the chi-square test. The relationship between the allele and genotype distribution of C3435T locus and the susceptibility, clinicopathological characteristics, curative effect and hematological toxicity of DLBCL were analyzed.1 the frequency of CT heterozygote and CC homozygote mutation was significantly higher in the case group (46.3% in CT genotype and 42.6% in CC genotype) compared to the control group (P < 0.05). The frequency of CC genotype mutation in the case group was 42.6%, which was significantly higher than that in the control group (P < 0.05, OR 3.209, 95% CI: 1.288-7.997). 2 the genotypes of C3435T locus of MDR1 gene were distributed in age, sex, nationality, pathological characteristics, clinical-stage, IPI index, B symptoms, infection with EB virus, clinicopathological characteristics and clinical efficacy of hepatitis B in patients with DLBCL. There was no significant difference in myelosuppression (P > 0.05).The homozygous mutation genotype of CC is the risk genotype of DLBCL. The alleles and genotypes are not associated with the clinicopathological characteristics, efficacy and myelosuppression toxicity of DLBCL.


Asunto(s)
Resistencia a Antineoplásicos/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , China , Femenino , Heterocigoto , Homocigoto , Humanos , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple
11.
Life Sci ; 259: 118212, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32768581

RESUMEN

AIMS: Autophagy plays a complex role in breast cancer by suppressing or improving the efficiency of treatment. Triple-negative breast cancer (TNBC) cell line (MDA-MB-231) is associated with aggressive response and developing therapy resistance. MDA-MB-231 cells depend on autophagy for survival. Also, the potential benefits of autophagy inhibition in ameliorating developed chemotherapy resistance towards MDA-MB-231 remains to be elucidated. Despite showing anti-tumorigenic activities, the use of lovastatin and docosahexaenoic acid (DHA) for treating different types of cancers is still limited. We aimed to investigate the protective effect of autophagy inhibition by chloroquine (CQ) in MDA-MB-231 cells resistance treated with lovastatin or DHA. MAIN METHODS: MDA-MB-231 cells were treated with 30 µM lovastatin and/or 100 µM DHA for 48 h plus 20 µM CQ. Autophagic flux was assessed in association with the expression of multidrug resistance gene 1 (MDR1), transforming growth factor beta 1 gene (TGF-ß1), and autophagy-related 7 gene (ATG7). KEY FINDINGS: Both drugs exhibited dose-dependent cytotoxicity, enhanced the autophagic flux represented by increased LC3BII protein concentration and decreased p62 protein concentration, and up-regulated the expression of MDR1, TGF-ß1, and ATG7 genes. CQ addition enhanced the cytotoxicity of drugs and inhibited the autophagic flux which is detected by higher levels of LC3BII and p62 correlated with the reverted MDR1, TGF-ß1 and ATG7 genes expression. SIGNIFICANCE: Autophagy inhibition by CQ showed an ameliorative effect on lovastatin- and DHA-induced resistance and enhanced their cytotoxicity, providing a promising strategy in breast cancer therapy.


Asunto(s)
Autofagia/efectos de los fármacos , Cloroquina/farmacología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Apoptosis/efectos de los fármacos , Autofagia/fisiología , Proteína 7 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cloroquina/metabolismo , Ácidos Docosahexaenoicos/farmacología , Femenino , Humanos , Lovastatina/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/fisiopatología
12.
Medicine (Baltimore) ; 99(29): e20582, 2020 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-32702814

RESUMEN

The morbidity of coronary artery disease (CAD) in the Uygur population of Xinjiang was much higher than the national average. Clopidogrel is the most commonly used medication worldwide in dual antiplatelet therapy for CAD, and the response of clopidogrel is affected by CYP2C19, PON1, and ABCB1 genetic polymorphisms. The distribution of CYP2C19*17, ABCB1, and PON1 genetic polymorphisms in Han and Uygur populations with CAD of Xinjiang has not been investigated.This study aimed to investigate the frequencies of CYP2C19, PON1, and ABCB1 genetic polymorphisms, and to identify the metabolizer phenotype of CYP2C19 in Han and Uygur populations with CAD in Northwestern Xinjiang, China. We identified 602 Han and 527 Uygur patients from 2014 through 2019 and studied genotypes for selected allele polymorphisms using sequencing by hybridization.There were significantly different allele frequencies and genotype frequencies between the 2 ethnic groups in terms of CYP2C19*2, *3, *17, ABCB1 and PON1, (P < .05). For CYP2C19*17, the frequency of TT genotype was 2.5% in Uygur patients, but it was undetectable in Han patients. In both the intermediate and poor metabolizer groups, the genotypes polymorphisms CYP2C19*2, *3, *17 were significantly less common in Uygur patients than in Han patients (P < .001). By contrast, the proportion of ultra-metabolizers as defined by CYP2C19*2, *3, *17 polymorphisms significantly higher in Uygur patients (18.6%) than in Han patients (1.7%, P < .001). The CYP2C19*2 frequency was significantly different between Han patients and Han healthy groups (P < .001), while the CYP2C19*3 frequency was significantly different between Uygur patients and Uygur healthy groups (P < .001).Our study supports the notion of interethnic differences in terms of CYP2C19, PON1, and ABCB1 polymorphisms and CYP2C19 genotype-defined clopidogrel metabolic groups. These finding could provide valuable data and insights into personalized CAD treatment for the Uygur and Han populations in Xinjiang.


Asunto(s)
Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/genética , Polimorfismo de Nucleótido Simple/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Anciano , Arildialquilfosfatasa/genética , China/etnología , Clopidogrel/uso terapéutico , Comorbilidad , Enfermedad de la Arteria Coronaria/mortalidad , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Grupos Étnicos/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico
14.
Cancer Res ; 80(14): 2996-3008, 2020 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-32536602

RESUMEN

Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. SIGNIFICANCE: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Interleucina-8/metabolismo , Neovascularización Patológica/patología , Paclitaxel/farmacología , Neoplasias de la Vejiga Urinaria/mortalidad , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Resistencia a Múltiples Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Quimioterapia de Inducción , Interleucina-8/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Neovascularización Patológica/inducido químicamente , Pronóstico , Tasa de Supervivencia , Células Tumorales Cultivadas , Neoplasias de la Vejiga Urinaria/irrigación sanguínea , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de Xenoinjerto
15.
Proc Natl Acad Sci U S A ; 117(27): 16009-16018, 2020 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-32571913

RESUMEN

Food and drug products contain diverse and abundant small-molecule additives (excipients) with unclear impacts on human physiology, drug safety, and response. Here, we evaluate their potential impact on intestinal drug absorption. By screening 136 unique compounds for inhibition of the key intestinal transporter OATP2B1 we identified and validated 24 potent OATP2B1 inhibitors, characterized by higher molecular weight and hydrophobicity compared to poor or noninhibitors. OATP2B1 inhibitors were also enriched for dyes, including 8 azo (R-N=N-R') dyes. Pharmacokinetic studies in mice confirmed that FD&C Red No. 40, a common azo dye excipient and a potent inhibitor of OATP2B1, decreased the plasma level of the OATP2B1 substrate fexofenadine, suggesting that FD&C Red No. 40 has the potential to block drug absorption through OATP2B1 inhibition in vivo. However, the gut microbiomes of multiple unrelated healthy individuals as well as diverse human gut bacterial isolates were capable of inactivating the identified azo dye excipients, producing metabolites that no longer inhibit OATP2B1 transport. These results support a beneficial role for the microbiome in limiting the unintended effects of food and drug additives in the intestine and provide a framework for the data-driven selection of excipients. Furthermore, the ubiquity and genetic diversity of gut bacterial azoreductases coupled to experiments in conventionally raised and gnotobiotic mice suggest that variations in gut microbial community structure may be less important to consider relative to the high concentrations of azo dyes in food products, which have the potential to saturate gut bacterial enzymatic activity.


Asunto(s)
Bacterias/metabolismo , Excipientes/metabolismo , Aditivos Alimentarios/metabolismo , Alimentos , Microbioma Gastrointestinal/fisiología , Absorción Intestinal/fisiología , Transportadores de Anión Orgánico/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Animales , Antialérgicos/metabolismo , Antialérgicos/farmacocinética , Compuestos Azo , Bacterias/aislamiento & purificación , Excipientes/farmacocinética , Femenino , Aditivos Alimentarios/farmacocinética , Antagonistas de los Receptores Histamínicos H1 no Sedantes/metabolismo , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacocinética , Humanos , Absorción Intestinal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Terfenadina/análogos & derivados
16.
Phys Chem Chem Phys ; 22(21): 12228-12238, 2020 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-32432253

RESUMEN

Light activated photosensitizers generate reactive oxygen species (ROS) that interfere with cellular components and can induce cell death, e.g., in photodynamic therapy (PDT). The effect of cellular components and especially proteins on the photochemistry and photophysics of the sensitizers is a key aspect in drug design and the correlating cellular response with the generation of specific ROS species. Here, we show the complex range of effects of binding of photosensitizer to a multidrug resistance protein, produced by bacteria, on the formers reactivity. We show that recruitment of drug like molecules by LmrR (Lactococcal multidrug resistance Regulator) modifies their photophysical properties and their capacity to induce oxidative stress especially in 1O2 generation, including rose bengal (RB), protoporphyrin IX (PpIX), bodipy, eosin Y (EY), riboflavin (RBF), and rhodamine 6G (Rh6G). The range of neutral and charged dyes with different exited redox potentials, are broadly representative of the dyes used in PDT.


Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Proteínas Bacterianas/metabolismo , Fármacos Fotosensibilizantes/química , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Sitios de Unión , Colorantes/metabolismo , Colorantes/efectos de la radiación , Lactococcus/química , Luz , Mutación , Fármacos Fotosensibilizantes/metabolismo , Fármacos Fotosensibilizantes/efectos de la radiación , Unión Proteica , Oxígeno Singlete/química
17.
Phytomedicine ; 71: 153239, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32447245

RESUMEN

BACKGROUND AND PURPOSE: Multidrug resistance (MDR) remains the main obstacle in cancer treatment and overexpression of P-glycoprotein (P-gp) is one of the most common causes of chemoresistance. The development of novel P-gp inhibitors from natural products is a prospective strategy to combat MDR cancers. Among the natural sesquiterpene compounds, sesquiterpene pyridine alkaloids exhibit various biological properties. Therefore, in the present study, we evaluated the modulatory effects of wilforine on P-gp expression and function. The molecular mechanisms and kinetic models of wilforine-mediated P-gp inhibition were further investigated. METHODS: The human P-gp stable expression cells (ABCB1/Flp-InTM-293) and human cervical cancer cells (sensitive: HeLaS3; MDR: KBvin) were used. The cell viability was assessed by SRB assay. The inhibitory effect of wilforine on P-gp efflux and the underlying mechanism were evaluated by assays for calcein-AM uptake, rhodamine123 and doxorubicin efflux, ATPase activity, real-time quantitative RT-PCR, apoptosis, and cell cycle analysis. Molecular docking was performed by the docking software CDOCKER with BIOVIA Discovery Studio 4.5 (D.S. 4.5). RESULTS: We found that wilforine significantly inhibited the efflux activity of P-gp in a concentration-dependent manner. Further kinetic analysis demonstrated that wilforine significantly inhibited P-gp efflux function by competitive inhibition and stimulated the basal P-gp ATPase activity. In addition, wilforine re-sensitized MDR cancer cells to chemotherapeutic drugs. The docking model indicated that wilforine was bound to residues of P-gp such as LEU884, LYS887, THR176 and ASN172. CONCLUSION: These results suggest a novel future therapeutic strategy for MDR cancer using wilforine as an adjuvant treatment with chemotherapy.


Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Lactonas/farmacología , Piridinas/farmacología , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/química , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos Fitogénicos/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/fisiología , Células HeLa , Humanos , Cinética , Lactonas/química , Simulación del Acoplamiento Molecular , Estudios Prospectivos , Piridinas/química
18.
Clin Drug Investig ; 40(7): 617-628, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32415468

RESUMEN

BACKGROUND: Validated genomic biomarkers for oncological drugs are expanding to improve targeted therapies. Pharmacogenetics research focusing on the mechanisms underlying imatinib suboptimal response might help to explain the different treatment outcomes and drug safety profiles. OBJECTIVE: To investigate whether polymorphisms in genes encoding cytochrome P450 (CYP) enzymes and ABCB1 transporter affect imatinib pharmacokinetic parameters. METHODS: A prospective, multicenter, pharmacogenetic pilot study was performed in the context of two separate oral imatinib bioequivalence clinical trials, which included 26 healthy volunteers. DNA was extracted in order to analyze polymorphisms in genes CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and ABCB1. Imatinib plasma concentrations were measured by HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods using WinNonlin software. RESULTS: Volunteers (n = 26; aged 24 ± 3 years; 69% male) presented regular pharmacokinetic imatinib data (concentration at 24 h, 436 ± 140 ng/mL and at 72 h, 40 ± 26 ng/mL; AUC0-72 32,868 ± 10,713 ng/mL⋅h; and Cmax 2074 ± 604 ng/mL). CYP2B6 516GT carriers showed a significant reduction of imatinib concentration at 24 h (23%, 391 ng/dL vs 511 ng/dL in 516GG carriers, p = 0.005) and elimination half-life (11%, 12.6 h vs 14.1 h in 516GG carriers, p = 0.041). Carriers for CYP3A4 (*22/*22, *1/*20 and *1/*22 variants) showed a reduced frequency of adverse events compared to *1/*1 carriers (0 vs 64%, p = 0.033). The other polymorphisms analyzed did not influence pharmacokinetics or drug toxicity. CONCLUSION: CYP2B6 G516T and CYP3A4 *20,*22 polymorphisms could influence imatinib plasma concentrations and safety profile, after single-dose administration to healthy subjects. This finding needs to be confirmed before it is implemented in clinical practice in oncological patients under treatment with imatinib.


Asunto(s)
Sistema Enzimático del Citocromo P-450/genética , Mesilato de Imatinib/farmacocinética , Polimorfismo Genético , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Adulto , Femenino , Voluntarios Sanos , Humanos , Mesilato de Imatinib/administración & dosificación , Masculino , Farmacogenética , Proyectos Piloto , Estudios Prospectivos , Adulto Joven
19.
PLoS One ; 15(5): e0227844, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32470043

RESUMEN

Morroniside is a biologically active polyphenol found in Cornus officinalis Sieb. et Zucc (CO) that exhibits a broad spectrum of pharmacological activities, such as protecting nerves, and preventing diabetic liver damage and renal damage. However, little data are available regarding the mechanism of its intestinal absorption. Here, an in vitro human intestinal epithelial cell model of cultured Caco-2 cells was applied to study the absorption and transport of morroniside. The effects of donor concentration, pH and inhibitors were investigated. The bidirectional permeability of morroniside from the apical (AP) to the basolateral (BL) side and in the reverse direction was studied. When administered at three tested concentrations (5, 25 and 100 µM), the apparent permeability coefficient (Papp) values in the AP-to-BL direction ranged from 1.59 × 10-6 to 2.66 × 10-6 cm/s. In the reverse direction, BL-to-AP, the value was ranged from 2.67 × 10-6 to 4.10 × 10-6 cm/s. The data indicated that morroniside transport was pH-dependent. The permeability of morroniside was affected by treatment with various inhibitors, such as multidrug resistance protein inhibitors MK571 and indomethacin, as well as the breast cancer resistance protein inhibitor apigenin. The mechanisms of the intestinal absorption of morroniside may involve multiple transport pathways, such as the passive diffusion and efflux protein-mediated active transport especially involving multidrug resistance protein 2 and breast cancer resistance protein. After the addition of CO, the Papp values in the AP-to-BL direction increased significantly, therefore, it can be assumed that some ingredients in the CO promote morroniside absorption in the small intestine.


Asunto(s)
Cornus/química , Glicósidos/farmacología , Absorción Intestinal/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Indometacina/farmacología , Absorción Intestinal/genética , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Neoplasias/patología , Permeabilidad/efectos de los fármacos , Propionatos/farmacología , Quinolinas/farmacología
20.
Int J Clin Pharmacol Ther ; 58(7): 375-386, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32301702

RESUMEN

OBJECTIVE: This study evaluated different influences of 14 single nucleotide polymorphisms (SNPs) and demographic factors leading to individual differences in the antihypertensive efficacy of felodipine in healthy Chinese subjects. MATERIALS AND METHODS: 24 subjects were sequenced for candidate SNPs. Plasma samples were obtained as clinical trial protocol, and were determined by a HPLC-MS/MS method. Pharmacokinetic parameters were calculated by WinNonlin 6.0. Statistical analysis was mainly performed by SPSS 22.0. A multiple linear regression model provided different weight coefficients of different demographic and genetic factors. RESULTS: The trend of Cmax is almost consistent with AUCss increase, but tmax of individuals is different; the antihypertensive effect of felodipine is individually different. A significant association was observed between systolic blood pressure decrease (ΔSBP) and SNPs of CACNA1C, CACNA1D, GNB3 respectively, while CACNA1C and CACNA1 were associated with diastolic blood pressure decrease (ΔDBP). CYP3A5 rs766746 and CYP3A4 rs2242480 were linked with Cmax and AUCss, and ABCB1 rs1045642 was associated with T1/2. Significant relationships were shown between AUCss and ΔSBP (p = 0.022) as well as Cmax and ΔSBP (p = 0.015). CONCLUSION: The efficacy of felodipine is individually different, influenced especially by CACNA1C rs1051375 and ABCB1 rs1045642. ΔDBP is associated with ΔSBP in multiple-dosing of felodipine in healthy Chinese subjects.


Asunto(s)
Antihipertensivos , Felodipino , Polimorfismo de Nucleótido Simple , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Antihipertensivos/farmacología , Grupo de Ascendencia Continental Asiática/genética , Canales de Calcio Tipo L/genética , Citocromo P-450 CYP3A , Felodipino/farmacología , Humanos , Espectrometría de Masas en Tándem
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