RESUMEN

PURPOSE: Tamoxifen, a widely used drug for breast cancer treatment, is associated with adverse effects on the liver, including the development of fatty liver. This study aimed to investigate the potential protective effect of caffeine against tamoxifen-induced fatty liver in Wistar rats. METHODS: Rats were divided into normal control, tamoxifen + saline, and tamoxifen + caffeine. Plasma samples were assessed for biochemical markers related to oxidative stress, inflammation, liver function, and cell damage. Additionally, liver histopathology was examined to quantify the extent of fatty infiltration. RESULTS: In the tamoxifen + saline group, elevated levels of plasma malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), alanine aminotransferase (ALT), cytokeratin 18, and soluble ST2 were observed compared to the normal control group, indicating increased oxidative stress, inflammation, and liver injury (p < 0.01). Moreover, histopathological examination revealed a significant increase in fatty infiltration (p < 0.001). However, in the tamoxifen + caffeine group, these markers were markedly reduced (p < 0.05, p < 0.01), and fatty infiltration was significantly mitigated (p < 0.001). CONCLUSIONS: The findings suggest that caffeine administration attenuates tamoxifen-induced fatty liver in rats by ameliorating oxidative stress, inflammation, liver injury, and cell damage. Histopathological evidence further supports the protective role of caffeine. This study highlights the potential of caffeine as a therapeutic intervention to counter tamoxifen-induced hepatic complications, contributing to the optimization of breast cancer treatment strategies.

Asunto(s)

Cafeína , Hígado Graso , Malondialdehído , Estrés Oxidativo , Ratas Wistar , Tamoxifeno , Animales , Cafeína/farmacología , Cafeína/uso terapéutico , Tamoxifeno/farmacología , Estrés Oxidativo/efectos de los fármacos , Malondialdehído/análisis , Hígado Graso/inducido químicamente , Hígado Graso/prevención & control , Hígado Graso/tratamiento farmacológico , Femenino , Hígado/efectos de los fármacos , Hígado/patología , Alanina Transaminasa/sangre , Ratas , Antineoplásicos Hormonales/farmacología , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/análisis , Biomarcadores/sangre , Biomarcadores/análisis , Modelos Animales de Enfermedad

RESUMEN

Luminal breast cancer has a high incidence worldwide and poses a severe health threat. Estrogen receptor alpha (ER-α) is activated by 17ß-estradiol (E2), and its overexpression promotes cancerous characteristics. Luminal breast cancer is an epithelial type; however, the cytokine IL-6, secreted by cells within the tumor microenvironment, stimulates the epithelial-to-mesenchymal transition (EMT) and promotes metastasis. Also, IL-6 decreases ER-α levels, favoring the tamoxifen (TMX) resistance development. However, genes under E2 regulation continue to be expressed even though this receptor is absent. GPR30 is an alternative E2 receptor present in both luminal and aggressive triple-negative breast cancer and is related to TMX resistance and cancer progression. The roles of GPR30 and IL-6 in metastasis have been individually established; however, their interplay remains unexplored. This study aims to elucidate the role of GPR30 in IL-6-induced metastatic properties of MCF-7 luminal breast cancer cells. Results showed that GPR30 contributes to the E2-induced MCF-7 proliferation because its inhibition with the antagonist G15 and the Pertussis toxin (PTX) reduced it. Besides, GPR30 upregulated vimentin and downregulated E-cadherin levels in MCF-7 and TMX-resistant (R-TMX) cells and is also involved in the IL-6-induced migration, invasion, and TMX resistance in MCF-7 cells. In addition, in MDA-MB-231 triple-negative cells, both basal and IL-6-induced metastatic properties were related to GPR30 activity. These results indicate that the GPR30 receptor regulates the EMT induced by IL-6 in breast cancer cells.

Asunto(s)

Neoplasias de la Mama , Transición Epitelial-Mesenquimal , Interleucina-6 , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Humanos , Interleucina-6/metabolismo , Interleucina-6/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Estrógenos/metabolismo , Femenino , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Células MCF-7 , Movimiento Celular/efectos de los fármacos , Metástasis de la Neoplasia , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Tamoxifeno/farmacología , Proliferación Celular/efectos de los fármacos

RESUMEN

BACKGROUND: Resveratrol, a natural compound, may be an alternative to improving conventional breast cancer therapy. Thus, we assessed the capability of resveratrol at a low dose to enhance the in vitro effect of conventional theray in estrogen receptor (ER) and human epidermal growth factor receptor type 2 (HER2)-positive breast cancer cells. METHODS: Cell viability of breast cancer cells was measured with neutral red uptake assay. Apoptosis, autophagy, cell cycle progression and cell proliferation were detected through hypotonic fluorescent solution assay, formation of acidic vesicular organelles, flow cytometry, and bromodeoxyuridine assay, respectively. Western blotting was performed to study the expression of pro-apoptotic, anti-apoptotic and autophagic proteins, and estrogen receptors. RESULTS: Resveratrol combined with tamoxifen metabolites or trastuzumab reduced cell viability of ER- and HER2-positive breast cancer cells, respectively. This effect was mainly associated with induction of apoptosis due to a greater formation of hypodiploid nuclei, reduced protein expression of procaspase-7, Bcl-2, Bcl-xL, and PARP; and increased expression of cleaved PARP. Resveratrol decreased the expression of ERα and increased that of ERß, contributing to the reduced viability on breast cancer cells. Combined treatments induced autophagy, evidenced by increased levels of acidic vesicular organelles and degradation of p62/SQSTM1 protein. Nevertheless, on inhibiting autophagy with 3-methyladenine, cell viability was further reduced and apoptosis was induced, suggesting a pro-survival role of autophagy, impairing apoptosis. CONCLUSIONS: Resveratrol increasead the in vitro cytotoxic effect of conventional therapy in breast cancer cells. However, it was necessary to block resveratrol-induced autophagy to improve the therapeutic response.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis , Autofagia , Neoplasias de la Mama , Proliferación Celular , Receptor ErbB-2 , Resveratrol , Tamoxifeno , Humanos , Resveratrol/farmacología , Resveratrol/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Apoptosis/efectos de los fármacos , Receptor ErbB-2/metabolismo , Autofagia/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proliferación Celular/efectos de los fármacos , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Receptores de Estrógenos/metabolismo , Línea Celular Tumoral , Sinergismo Farmacológico , Células MCF-7 , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos

RESUMEN

PURPOSE: Inhibitor of differentiation 4 (ID4) is a dominant-negative regulator of basic helix-loop-helix (bHLH) transcription factors. The expression of ID4 is dysregulated in various breast cancer subtypes, indicating a potential role for ID4 in subtype-specific breast cancer development. This study aims to elucidate the epigenetic regulation of ID4 within breast cancer subtypes, with a particular focus on DNA methylation and chromatin accessibility. METHODS: Bioinformatic analyses were conducted to assess DNA methylation and chromatin accessibility in ID4 regulatory regions across breast cancer subtypes. Gene Set Enrichment Analysis (GSEA) was conducted to identify related gene sets. Transcription factor binding within ID4 enhancer and promoter regions was explored. In vitro experiments involved ER+ breast cancer cell lines treated with estradiol (E2) and Tamoxifen. RESULTS: Distinct epigenetic profiles of ID4 were observed, revealing increased methylation and reduced chromatin accessibility in luminal subtypes compared to the basal subtype. Gene Set Enrichment Analysis (GSEA) implicated estrogen-related pathways, suggesting a potential link between estrogen signaling and the regulation of ID4 expression. Transcription factor analysis identified ER and FOXA1 as regulators of ID4 enhancer regions. In vitro experiments confirmed the role of ER, demonstrating reduced ID4 expression and increased methylation with estradiol treatment. Conversely, Tamoxifen treatment increased ID4 expression, indicating the potential involvement of ER signaling through ERα in the epigenetic regulation of ID4 in breast cancer cells. CONCLUSION: This study shows the intricate epigenetic regulation of ID4 in breast cancer, highlighting subtype-specific differences in DNA methylation and chromatin accessibility.

Asunto(s)

Neoplasias de la Mama , Cromatina , Biología Computacional , Metilación de ADN , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Factor Nuclear 3-alfa del Hepatocito , Proteínas Inhibidoras de la Diferenciación , Regiones Promotoras Genéticas , Humanos , Proteínas Inhibidoras de la Diferenciación/genética , Proteínas Inhibidoras de la Diferenciación/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Biología Computacional/métodos , Cromatina/metabolismo , Cromatina/genética , Factor Nuclear 3-alfa del Hepatocito/genética , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Línea Celular Tumoral , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Elementos de Facilitación Genéticos , Estradiol/farmacología

RESUMEN

Drug repositioning is an alternative to overcome the complexity of the drug discovery and approval procedures for the treatment of Mycobacterium abscessus Complex (MABSC) infections that are increasing globally due to the emergency of antimicrobial resistance mechanisms. Here, an in silico chemogenomics approach was performed to compare the sequences from 4942 M. abscessus subsp. abscessus (M. abscessus) proteins with 5258 or 3473 therapeutic targets registered in the DrugBank or Therapeutic Target Database, respectively. This comparison identified 446 drugs or drug candidates whose targets were homologous to M. abscessus proteins. These identified drugs were considered potential inhibitors of MABSC (anti-MABSC activity). Further screening and inspection resulted in the selection of ezetimibe, furosemide, itraconazole, miconazole (MCZ), tamoxifen (TAM), and thiabendazole (THI) for experimental validation. Among them, MCZ and TAM showed minimum inhibitory concentrations (MIC) of 32 and 24 µg mL-1 against M. abscessus, respectively. For M. bolletii and M. massiliense strains, MCZ and TAM showed MICs of 16 and 24 µg mL-1, in this order. Subsequently, the antibacterial activity of MCZ was confirmed in vivo, indicating its potential to reduce the bacterial load in the lungs of infected mice. These results show that MCZ and TAM can serve as molecular scaffolds for the prospective hit-2-lead optimization of new analogs with greater potency, selectivity, and permeability.

Asunto(s)

Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Animales , Ratones , Mycobacterium abscessus/genética , Miconazol/farmacología , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Reposicionamiento de Medicamentos , Estudios Prospectivos , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico , Infecciones por Mycobacterium no Tuberculosas/microbiología , Antibacterianos/farmacología , Pruebas de Sensibilidad Microbiana

RESUMEN

The chemokine stromal cell-derived-factor 1 (SDF)-1/CXCL12 acts by binding to its receptors, the CXC-4 chemokine receptor (CXCR4) and the CXC-7 chemokine receptor (CXCR7). The binding of CXCL12 to its receptors results in downstream signaling that leads to cell survival, proliferation and migration of tumor cells. CXCL12 and CXCR4 are highly expressed in breast cancer (BC) and glioblastoma (GBM) compared to normal cells. High expression of this chemokine axis correlates with increased therapy resistance and grade, tumor spread and poorer prognosis in these tumors. Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) that inhibits the expression of estrogen-regulated genes, including growth and angiogenic factors secreted by tumor cells. Additionally, TMX targets several proteins, such as protein kinase C (PKC), phospholipase C (PLC), P-glycoprotein (PgP), phosphatidylinositol-3-kinase (PI3K) and ion channels. This drug showed promising antitumor activity against both BC and GBM cells. In this review, we discuss the role of the CXCL12-CXCR4-CXCR7 chemokine axis in BC and GBM tumor biology and propose TMX as a potential modulator of this axis in these tumors. TMX modulates the CXCL12-CXCR4-CXCR7 axis in BC, however, there are no studies on this in GBM. We propose that studying this axis in GBM cells/patients treated with TMX might be beneficial for these patients. TMX inhibits important signaling pathways in these tumors and the activation of this chemokine axis is associated with increased therapy resistance.

Asunto(s)

Neoplasias de la Mama , Glioblastoma , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Tamoxifeno/farmacología , Tamoxifeno/uso terapéutico , Glioblastoma/tratamiento farmacológico , Transducción de Señal , Fosfatidilinositol 3-Quinasa , Quimiocina CXCL12 , Receptores CXCR4

RESUMEN

CKD progression depends on the activation of an intricate set of hemodynamic and inflammatory mechanisms, promoting renal leukocyte infiltration, inflammation and fibrosis, leading to renal function loss. There are currently no specific drugs to detain renal fibrogenesis, which is a common end-point for different nephropathies. Clinical therapy for CKD is mostly based on the management of hypertension and proteinuria, partially achieved with renin-angiotensin-aldosterone system (RAAS) blockers, and the control of inflammation by immunosuppressive drugs. The aim of the present study was to verify if the administration of tamoxifen (TAM), an estrogen receptor modulator, clinically employed in the treatment of breast cancer and predicted to exert antifibrotic effects, would promote additional benefits when associated to a currently used therapeutic scheme for the conservative management of experimental CKD. Wistar rats underwent the NAME model of hypertensive nephrosclerosis, obtained by daily oral administration of a nitric oxide synthesis inhibitor, associated to dietary sodium overload. The therapeutic association of TAM to losartan (LOS), and mofetil mycophenolate (MMF) effectively reduced the severe hypertension, marked albuminuria and glomerular damage exhibited by NAME animals. Moreover, the association also succeeded in limiting renal inflammation in this model, and promoted further reduction of ECM interstitial accumulation and renal fibrosis, compared to the monotherapies. According to our results, the association of TAM to the currently used conservative treatment of CKD added significant antifibrotic effects both in vivo and in vitro, and may represent an alternative to slow the progression of chronic nephropathy.

Asunto(s)

Hipertensión , Nefroesclerosis , Insuficiencia Renal Crónica , Ratas , Animales , Ratas Wistar , Nefroesclerosis/tratamiento farmacológico , Nefroesclerosis/etiología , Tratamiento Conservador , Tamoxifeno/farmacología , Insuficiencia Renal Crónica/tratamiento farmacológico , Inflamación

RESUMEN

BACKGROUND: The purpose of this preclinical study was to evaluate the influence of tamoxifen (TAM) on the peri-implant bone remodeling of osseointegrated titanium implants in ovariectomized female rats. MATERIALS AND METHODS: Seventy-two female rats underwent bilateral ovariectomy 20 weeks before implants placement. One titanium implant was inserted in each tibia of the animals. Six weeks following the implant surgery, animals were randomly divided into two experimental groups (n = 36), which received either saline solution (SS) or tamoxifen citrate (TAM) via gavage until euthanasia. Euthanasia was performed at 30, 60, and 90 days after the first gavage. Assessments of bone to implant contact (BIC), bone ingrowth percentage (BIN), morphological description of cellular and tissue reactions, immunohistochemistry for the detection of bone morphogenetic protein 2/4 (BMP2/4), runt-related transcription factor 2 (RUNX-2), osteocalcin (OCN) and tartrate-resistant acid phosphatase (TRAP), and bone chemical composition through scanning electron microscopy with energy-dispersive x-ray spectroscopy were performed. RESULTS: Tamoxifen group presented higher BIC, higher BIN, higher RUNX-2 and OCN, lower TRAP-positive cells/mm2 , and no differences regarding BMP-2/4 positive cells/mm2 than SS group in all periods. TAM group also showed higher Ca/P rate than SS group. CONCLUSION: Tamoxifen enhanced the remodeling of the bone surrounding titanium implants in ovariectomized rats.

Asunto(s)

Implantes Dentales , Titanio , Animales , Femenino , Ratas , Homeostasis , Oseointegración , Osteocalcina , Tamoxifeno/farmacología , Tibia/cirugía , Titanio/química

RESUMEN

INTRODUCCIÓN: En Perú, la prevalencia de la depresión en mujeres con cáncer de mama (estadío I o II) ha sido reportada en un rango de 21.9% a 25.6%, y por niveles en un 16.9% para síntomas leves, 6.3% moderado y 2.4% severo. El tratamiento antidepresivo usado en primera línea, como los Inhibidores selectivos de la recaptación de serotonina, inhiben la CYP2D6 en diferentes grados. Los nuevos agentes antidepresivos han mostrado un mejor perfil en su prescripción conjunta. Algunos recomiendan evitar fármacos como la paroxetina y fluoxetina para el tratamiento conjunto. La literatura sugiere que los antidepresivos más seguros son la Venlafaxina, Desvenlafaxina y Mirtazapina. CUADRO CLÍNICO: El tratamiento de la depresión, preferentemente moderada a severa, de primera línea es el uso de IRSS, así como nuevos agentes que han mostrado menor efecto adverso y mayor eficacia. En mujeres, el uso del Tamoxifeno puede inducir síntomas propios de la menopausia y se ha reportado eficacia de antidepresivos como la Venlafaxina para el tratamiento de los sofocos en conjunto con el Tamoxifeno. La coprescripción de la Desvenlafaxina y el Tamoxifeno se ha sugerido por su baja concentración en el plasma, aunque la evidencia no sea suficiente. TECNOLOGÍA SANITARIA: La Desvenlafaxina es el principal metabolito activo de la Venlafaxina, es un antidepresivo de la clase de los inhibidores de la recaptación de serotonina y norepinefrina. La desvenlafaxina inhibe la recaptación de neurotransmisores en los transportadores de serotonina, noradrenalina y dopamina. La Desvenlafaxina inhibe los transportadores de serotonina y con una afinidad 10 veces superior a la de los transportadores de noradrenalina y los transportadores de dopamina con la menor afinidad. Se puede utilizar para el tratamiento de depresión mayor en adultos y síntomas como el sofoco en mujeres pre y pos menopáusicas. Está formulado como un comprimido de liberación prolongada. OBJETIVO: Evaluar la eficacia y seguridad, así como documentos relacionados a la decisión de cobertura de la Desvenlafaxina en pacientes con cáncer de mama comparado a otros antidepresivos. METODOLOGÍA: Se realizó una búsqueda sistemática en las bases de datos bibliográficas: MEDLINE (PubMed), LILACS, Cochrane Library, así como en buscadores genéricos de Internet incluyendo Google Scholar. Así también, se hizo una búsqueda en agencias que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC). RESULTADOS: Se identificó un ensayo clínico abierto y dos GPC. No se encontraron ETS o Evaluaciones económicas en la región. CONCLUSIONES: La evidencia en relación a la interacción de la Desvenlafaxina y el uso del Tamoxifeno concomitante es insuficiente. Un único estudio de tipo farmacocinético, con el uso concomitante, no alteró la concentración minima, reciente y máxima de la Desvenlafaxina. Las guías de práctica clínica identificadas, en general, recomiendan el uso (o coprescripción) de la Desvenlafaxina en mujeres con cáncer de mama usuarias de Tamoxifeno por su nivel de eficacia semejante a otros Inhibidores de Recaptación de Noradrenalina y la baja concentración en plasma del endoxifeno. El nivel de concentración mínima reportada se sugiere como un parámetro, farmacocinético y farmacodinámico, a favor al momento de tomar la decisión de la elección del fármaco y su posología. Las guías de práctica clínica identificadas, en general, recomiendan el uso (o coprescripción) de la Desvenlafaxina en mujeres con cáncer de mama usuarias de Tamoxifeno por su nivel de eficacia semejante a otros Inhibidores de recaptación de Noradrenalina y la baja concentración en plasma del endoxifeno. Cuando sea posible, se recomienda el uso de Citalopram, Escitalopram, Venlafaxina y Desvenlafaxina, dosis bajas de Sertralina o Mirtazapina como antidepresivos de primera línea. Finalmente y de modo general, se recomienda no usar antidepresivos de forma rutinaria para el tratamiento de depresión leve o subclínica, más bien considerar el nivel de severidad, principalmente en el tratamiento de la depresión severa.

Asunto(s)

Humanos , Tamoxifeno/farmacología , Neoplasias de la Mama/patología , Depresión/tratamiento farmacológico , Succinato de Desvenlafaxina/uso terapéutico , Eficacia , Análisis Costo-Beneficio , Interacciones Farmacológicas

RESUMEN

AIMS: The present study aimed to verify the effects of resistance training (RT) and successive detraining on body composition, muscle strength and lipid profile as primary outcome, and the oxidative stress and inflammatory markers as second outcome of postmenopausal Breast Cancer (BC) survivors undergoing tamoxifen (TA). MAIN METHODS: Fourteen postmenopausal BC survivors underwent 12 weeks of resistance exercise training and subsequently 12 weeks of detraining. Anthropometric parameters, lipid profile, muscle strength, inflammatory cytokines and the oxidative stress markers, were assessed before, after the training period and after detraining period. KEY FINDINGS: One-way ANOVA showed that fat mass decrease (39.4 ± 6.9 to 37.7 ± 6.8%) and free-fat mass increase (39.3 ± 4.9 to 40.3 ± 5.6%) after RT. Muscle strength increased in response to training but decreased after the detraining period. Triglycerides (156 ± 45 to 123 ± 43 mg/dL) and total cholesterol (202 ± 13 to 186 ± 16 mg/dL) decreased after the RT and HDL-cholesterol (47 ± 9 to 56 ± 9 mg/dL) increased after RT and remained higher (53 ± 10 mg/dL) than after detraining. IL-6 increases (24.65 ± 10.85 to 41.42 ± 22.88 pg/mL) and IL-17 (2.42 ± 0.32 to 1.69 ± 0.19 pg/mL), TBARS (1.91 ± 0.19 to 1.03 ± 0.1 µmol/L), SOD (24.65 ± 10.85 to 41.42 ± 22.88 U/gHb) and Catalase activity (445.9 ± 113.0 to 345.8 ± 81.7 k/gHb·s) reduced after RT and remained lower after detraining. SIGNIFICANCE: Resistance exercise training improves health markers of BC survivors undergoing TA and detraining are not sufficient to reverse the positive effects in oxidative stress markers.

Asunto(s)

Biomarcadores de Tumor/sangre , Composición Corporal , Neoplasias de la Mama/fisiopatología , Supervivientes de Cáncer , Ejercicio Físico , Lípidos/sangre , Fuerza Muscular , Tamoxifeno/uso terapéutico , Adulto , Anciano , Composición Corporal/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Inflamación/patología , Persona de Mediana Edad , Fuerza Muscular/efectos de los fármacos , Tamoxifeno/farmacología

RESUMEN

Cytotoxic effects of cannabidiol (CBD) and tamoxifen (TAM) have been observed in several cancer types. We have recently shown that CBD primarily targets mitochondria, inducing a stable mitochondrial permeability transition pore (mPTP) and, consequently, the death of acute lymphoblastic leukemia (T-ALL) cells. Mitochondria have also been documented among cellular targets for the TAM action. In the present study we have demonstrated a synergistic cytotoxic effect of TAM and CBD against T-ALL cells. By measuring the mitochondrial membrane potential (ΔΨm), mitochondrial calcium ([Ca2+]m) and protein-ligand docking analysis we determined that TAM targets cyclophilin D (CypD) to inhibit mPTP formation. This results in a sustained [Ca2+]m overload upon the consequent CBD administration. Thus, TAM acting on CypD sensitizes T-ALL to mitocans such as CBD by altering the mitochondrial Ca2+ homeostasis.

Asunto(s)

Calcio/metabolismo , Cannabidiol/farmacología , Peptidil-Prolil Isomerasa F/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Tamoxifeno/farmacología , Línea Celular Tumoral , Peptidil-Prolil Isomerasa F/química , Sinergismo Farmacológico , Homeostasis/efectos de los fármacos , Humanos , Células Jurkat , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Poro de Transición de la Permeabilidad Mitocondrial/metabolismo , Modelos Moleculares , Simulación del Acoplamiento Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Conformación Proteica

RESUMEN

A series of benzo [d] [1,3] azoles 2-substituted with benzyl- and allyl-sulfanyl groups were synthesized, and their cytotoxic activities were in vitro evaluated against a panel of six human cancer cell lines. The results showed that compounds BTA-1 and BMZ-2 have the best inhibitory effects, compound BMZ-2 being comparable in some cases with the reference drug tamoxifen and exhibiting a low cytotoxic effect against healthy cells. In silico molecular coupling studies at the tamoxifen binding site of ERα and GPER receptors revealed affinity and the possible mode of interaction of both compounds BTA-1 and BMZ-2.

Asunto(s)

Antineoplásicos/química , Antineoplásicos/metabolismo , Azoles/química , Azoles/metabolismo , Citotoxinas/química , Citotoxinas/metabolismo , Simulación del Acoplamiento Molecular/métodos , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Azoles/síntesis química , Azoles/farmacología , Sitios de Unión , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citotoxinas/síntesis química , Citotoxinas/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Receptor alfa de Estrógeno/metabolismo , Humanos , Células MCF-7 , Estructura Molecular , Células PC-3 , Relación Estructura-Actividad , Tamoxifeno/metabolismo , Tamoxifeno/farmacología

RESUMEN

Background: Praziquantel is the only drug available to treat schistosomiasis, and there is an urgent demand for new anthelmintic agents. Methodology & results: We conducted in-depth in vitro and in vivo studies and report a target fishing investigation. In vitro, tamoxifen was active against adult and immature worms at low concentrations (<5 µM). Tamoxifen at a single dose (400 mg/kg) or once daily for five consecutive days (100 mg/kg/day) in mice harboring either adult (patent infection) or juvenile (prepatent infection) significantly reduced worm burden (30-70%) and egg production (70-90%). Target fishing studies revealed propionyl-CoA carboxylase as a potential target for tamoxifen in Schistosoma mansoni and glucose uptake by S. mansoni was also significantly reduced. Conclusion: Our results provide news evidence of antiparasitic effect of tamoxifen and reveal propionyl-CoA carboxylase as a potential target.

Asunto(s)

Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis/tratamiento farmacológico , Esquistosomicidas/farmacología , Tamoxifeno/farmacología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Esquistosomicidas/química , Tamoxifeno/química

RESUMEN

The estrogen receptor alpha (ERα) is a ligand-activated transcription factor whose activity is modulated by its interaction with multiple protein complexes. In this work, we have identified the protein interferon alpha inducible protein 27 (IFI27/ISG12) as a novel ERα-associated protein. IFI27/ISG12 transcription is regulated by interferon and estradiol and its overexpression is associated to reduced overall survival in ER+ breast cancer patients but its function in mammary gland tissue remains elusive. In this study we showed that overexpression of IFI27/ISG12 in breast cancer cells attenuates ERα transactivation activity and the expression of ERα-dependent genes. Our results demonstrated that IFI27/ISG12 overexpression in MCF-7 cells reduced their proliferation rate in 2-D and 3-D cell culture assays and impaired their ability to migrate in a wound-healing assay. We show that IFI27/ISG12 downregulation of ERα transactivation activity is mediated by its ability to facilitate the interaction between ERα and CRM1/XPO1 that mediates the nuclear export of large macromolecules to the cytoplasm. IFI27/ISG12 overexpression was shown to impair the estradiol-dependent proliferation and tamoxifen-induced apoptosis in breast cancer cells. Our results suggest that IFI27/ISG12 may be an important factor in regulating ERα activity in breast cancer cells by modifying its nuclear versus cytoplasmic protein levels. We propose that IFI27/ISG12 may be a potential target of future strategies to control the growth and proliferation of ERα-positive breast cancer tumors.

Asunto(s)

Neoplasias de la Mama/metabolismo , Regulación hacia Abajo/fisiología , Receptor alfa de Estrógeno/biosíntesis , Carioferinas/biosíntesis , Proteínas de la Membrana/biosíntesis , Receptores Citoplasmáticos y Nucleares/biosíntesis , Activación Transcripcional/fisiología , Neoplasias de la Mama/genética , Bases de Datos Genéticas , Regulación hacia Abajo/efectos de los fármacos , Estradiol/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Carioferinas/genética , Células MCF-7 , Proteínas de la Membrana/genética , Receptores Citoplasmáticos y Nucleares/genética , Tamoxifeno/farmacología , Activación Transcripcional/efectos de los fármacos , Proteína Exportina 1

RESUMEN

Reconsolidation is a time-limited process under which reactivated memory content can be modified. Works focused on studying reconsolidation mainly restrict intervention to the moments immediately after reactivation and to recently acquired memories. However, the brain areas activated during memory retrieval depend on when it was acquired, and it is relatively unknown how different brain sites contribute to reconsolidation and persistence of reactivated recent and remote fear memories. Here, we sought to investigate the participation of prelimbic (PL) and anterior cingulate cortices (ACC) in recent (1 d old) and remote (21 d old) fear memory reconsolidation and persistence. Male Wistar rats were submitted to the contextual fear conditioning protocol. Tamoxifen (TMX), an estrogen receptor modulator known to inhibit protein kinase C activity was used to interfere with these processes. When infused into the PL cortex, but not into the ACC, TMX administration immediately or 6 h after recent fear memory reactivation impaired memory reconsolidation and persistence, respectively. TMX administered immediately after remote memory reactivation impaired memory reconsolidation when infused into the PL cortex and ACC. However, remote memory persistence was only affected when TMX was infused 6 h after memory reactivation into the ACC and no effect was observed when TMX was infused 6 h after memory reactivation into PL cortex. Together, the findings provide further evidence on the participation of PL cortex and ACC in reconsolidation of recent and remote fear memories and suggest that the persistence of a reactivated fear memory becomes independent on the PL cortex with memory age and dependent on the ACC.

Asunto(s)

Miedo/fisiología , Giro del Cíngulo/fisiología , Consolidación de la Memoria/fisiología , Memoria a Largo Plazo/fisiología , Memoria a Corto Plazo/fisiología , Recuerdo Mental/fisiología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Giro del Cíngulo/efectos de los fármacos , Masculino , Consolidación de la Memoria/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Ratas , Ratas Wistar , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tamoxifeno/farmacología , Factores de Tiempo

RESUMEN

Neutrophils participate in innate immunity as the first line of host defence against microorganisms. However, persistent neutrophil activity and delayed apoptosis can be harmful to surrounding tissues; this problem occurs in diverse inflammatory diseases, including asthma-affected horses. Previous studies in horses with acute lung inflammation indicated that treatment with tamoxifen (TX), a selective oestrogen receptor modulator, produces a significant decrease in bronchoalveolar lavage fluid (BALF) neutrophil content. The aim of this study was to investigate the effect of tamoxifen and its metabolites (N-desmethyltamoxifen and endoxifen) on the mitochondrial membrane potential assay by flow cytometry, and the activation of effector caspase-3 through immunoblotting, in peripheral blood neutrophils obtained from healthy horses (n = 5). Results show that tamoxifen, N-desmethyltamoxifen and endoxifen depolarize the mitochondrial membrane and activate caspase-3 in healthy equine neutrophils in vitro. These findings suggest that tamoxifen and its metabolites may activate the intrinsic apoptotic pathway in equine neutrophils. However, more studies are necessary to further explore the signalling pathways of these drugs in the induction of apoptosis.

Asunto(s)

Antiasmáticos/farmacología , Caspasa 3/inmunología , Caballos/inmunología , Inmunidad Innata/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacología , Animales , Femenino , Citometría de Flujo/veterinaria , Immunoblotting/veterinaria , Masculino , Membranas Mitocondriales/fisiología , Neutrófilos/inmunología

RESUMEN

BACKGROUND: Tamoxifen (Tam) is the most frequent treatment for estrogen receptor (ER) positive breast cancer. We recently showed that fibronectin (FN) leads to Tam resistance and selection of breast cancer stem cells. With the aim of developing a nanoformulation that would simultaneously tackle ER and FN/ß1 integrin interactions, we designed polyethylene glycol-polycaprolactone polymersomes polymersomes (PS) that carry Tam and are functionalized with the tumor-penetrating iRGD peptide (iRGD-PS-Tam). RESULTS: Polyethylene glycol-polycaprolactone PS were assembled and loaded with Tam using the hydration film method. The loading of encapsulated Tam, measured by UPLC, was 2.4 ± 0.5 mol Tam/mol polymer. Physicochemical characterization of the PS demonstrated that iRGD functionalization had no effect on morphology, and a minimal effect on the PS size and polydispersity (176 nm and Pdi 0.37 for iRGD-TAM-PS and 171 nm and Pdi 0.36 for TAM-PS). iRGD-PS-Tam were taken up by ER+ breast carcinoma cells in 2D-culture and exhibited increased penetration of 3D-spheroids. Treatment with iRGD-PS-Tam inhibited proliferation and sensitized cells cultured on FN to Tam. Mechanistically, treatment with iRGD-PS-Tam resulted in inhibition ER transcriptional activity as evaluated by a luciferase reporter assay. iRGD-PS-Tam reduced the number of cells with self-renewing capacity, a characteristic of breast cancer stem cells. In vivo, systemic iRGD-PS-Tam showed selective accumulation at the tumor site. CONCLUSIONS: Our study suggests iRGD-guided delivery of PS-Tam as a potential novel therapeutic strategy for the management of breast tumors that express high levels of FN. Future studies in pre-clinical in vivo models are warranted.

Asunto(s)

Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Portadores de Fármacos/química , Oligopéptidos/química , Receptores de Estrógenos/metabolismo , Tamoxifeno/administración & dosificación , Animales , Antineoplásicos Hormonales/farmacocinética , Antineoplásicos Hormonales/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Autorrenovación de las Células/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Ratones Desnudos , Poliésteres/química , Polietilenglicoles/química , Tamoxifeno/farmacocinética , Tamoxifeno/farmacología , Activación Transcripcional/efectos de los fármacos

RESUMEN

BACKGROUND: Peritoneal fibrosis (PF) represents a long-term complication of peritoneal dialysis (PD), affecting peritoneal membrane (PM) integrity and function. Understanding the mechanisms underlying PF development in an uremic environment aiming alternative therapeutic strategies for treating this process is of great interest. The aim of this study was to analyze the effects of tamoxifen (TAM) and recombinant BMP7 (rBMP7) in an experimental model of PF developed in uremic rats. METHODS: To mimic the clinical situation of patients on long-term PD, a combo model, characterized by the combination of PF and CKD with severe uremia, was developed in Wistar rats. PF was induced by intraperitoneal (IP) injections of chlorhexidine gluconate (CG), and CKD was induced by an adenine-rich diet. Uremia was confirmed by severe hypertension, increased blood urea nitrogen (BUN> 120 mg/dL) and serum creatinine levels (> 2 mg/dL). Uremic rats with PF were treated with TAM (10 mg/Kg by gavage) or BMP7 (30 µg/Kg, IP). Animals were followed up for 30 days. RESULTS: CG administration in uremic rats induced a striking increase in PM thickness, neoangiogenesis, demonstrated by increased capillary density, and failure of ultrafiltration capacity. These morphological and functional changes were blocked by TAM or rBMP7 treatment. In parallel, TAM and rBMP7 significantly ameliorated the PM fibrotic response by reducing α-SMA, extracellular matrix proteins and TGF-ß expression. TAM or rBMP7 administration significantly inhibited peritoneal Smad3 expression in uremic rats with PF, prevented Smad3 phosphorylation, and induced a remarkable up-regulation of Smad7, an intracellular inhibitor of TGFß/Smad signaling, contributing to a negative modulation of profibrotic genes. Both treatments were also effective in reducing local inflammation, possibly by upregulating IκB-α expression in the PM of uremic rats with PF. In vitro experiments using primary peritoneal fibroblasts activated by TGF-ß confirmed the capacity of TAM or rBMP7 in blocking inflammatory mediators, such as IL-1ß expression. CONCLUSIONS: In conclusion, these findings indicate important roles of TGF-ß/Smad signaling in PF aggravated by uremia, providing data regarding potential therapeutic approaches with TAM or rBMP7 to block this process.

Asunto(s)

Proteína Morfogenética Ósea 7/farmacología , Inflamación/metabolismo , Fibrosis Peritoneal/metabolismo , Tamoxifeno/farmacología , Uremia/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Masculino , Peritoneo/citología , Peritoneo/efectos de los fármacos , Ratas , Ratas Wistar , Proteínas Recombinantes/farmacología , Insuficiencia Renal Crónica , Proteína smad7 , Factor de Crecimiento Transformador beta/metabolismo

RESUMEN

This study shows the effects of tamoxifen, a known estrogen receptor antagonist used in the treatment of breast cancer, on the sphingolipid pathway of Trypanosoma cruzi, searching for potential chemotherapeutic targets. A dose-dependent epimastigote growth inhibition at increasing concentration of tamoxifen was determined. In blood trypomastigotes, treatment with 10 µM showed 90% lysis, while 86% inhibition of intracellular amastigote development was obtained using 50 µM. Lipid extracts from treated and non-treated metabolically labelled epimastigotes evidenced by thin layer chromatography different levels of sphingolipids and MALDI-TOF mass spectrometry analysis assured the identity of the labelled species. Comparison by HPLC-ESI mass spectrometry of lipids, notably exhibited a dramatic increase in the level of ceramide in tamoxifen-treated parasites and a restrained increase of ceramide-1P and sphingosine, indicating that the drug is acting on the enzymes involved in the final breakdown of ceramide. The ultrastructural analysis of treated parasites revealed characteristic morphology of cells undergoing an apoptotic-like death process. Flow cytometry confirmed cell death by an apoptotic-like machinery indicating that tamoxifen triggers this process by acting on the parasitic sphingolipid pathway.

Asunto(s)

Antiprotozoarios/farmacología , Estadios del Ciclo de Vida/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Esfingolípidos/antagonistas & inhibidores , Tamoxifeno/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Ceramidas/antagonistas & inhibidores , Ceramidas/biosíntesis , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Reposicionamiento de Medicamentos , Antagonistas de Estrógenos/farmacología , Ratones , Ratones Endogámicos BALB C , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Esfingolípidos/biosíntesis , Esfingosina/antagonistas & inhibidores , Esfingosina/biosíntesis , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/metabolismo

RESUMEN

Tamoxifen (TAM) is a first generation-SERM administered for hormone receptor-positive (HER+) breast cancer in both pre- and post-menopausal patients and may undergo metabolic activation in organisms that share similar receptors and thus face comparable mechanisms of response. The present study aimed to assess whether environmental trace concentrations of TAM are bioavailable to the filter feeder M. galloprovincialis (100 ng L-1) and to the deposit feeder N. diversicolor (0.5, 10, 25 and 100 ng L-1) after 14 days of exposure. Behavioural impairment (burrowing kinetic), neurotoxicity (AChE activity), endocrine disruption by alkali-labile phosphate (ALP) content, oxidative stress (SOD, CAT, GPXs activities), biotransformation (GST activity), oxidative damage (LPO) and genotoxicity (DNA damage) were assessed. Moreover, this study also pertained to compare TAM cytotoxicity effects to mussels and targeted human (i.e. immortalized retinal pigment epithelium - RPE; and human transformed endothelial cells - HeLa) cell lines, in a range of concentrations from 0.5 ng L-1 to 50 µg L-1. In polychaetes N. diversicolor, TAM exerted remarkable oxidative stress and damage at the lowest concentration (0.5 ng L-1), whereas significant genotoxicity was reported at the highest exposure level (100 ng L-1). In mussels M. galloprovincialis, 100 ng L-1 TAM caused endocrine disruption in males, neurotoxicity, and an induction in GST activity and LPO byproducts in gills, corroborating in genotoxicity over the exposure days. Although cytotoxicity assays conducted with mussel haemocytes following in vivo exposure was not effective, in vitro exposure showed to be a feasible alternative, with comparable sensitivity to human cell line (HeLa).

Asunto(s)

Tamoxifeno/farmacología , Animales , Biotransformación , Bivalvos , Daño del ADN , Femenino , Branquias , Humanos , Masculino , Estrés Oxidativo/efectos de los fármacos