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1.
Cell Rep Med ; 5(4): 101504, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38593809

RESUMEN

Targeted therapies have improved outcomes for certain cancer subtypes, but cytotoxic chemotherapy remains a mainstay for triple-negative breast cancer (TNBC). The epithelial-to-mesenchymal transition (EMT) is a developmental program co-opted by cancer cells that promotes metastasis and chemoresistance. There are no therapeutic strategies specifically targeting mesenchymal-like cancer cells. We report that the US Food and Drug Administration (FDA)-approved chemotherapeutic eribulin induces ZEB1-SWI/SNF-directed chromatin remodeling to reverse EMT that curtails the metastatic propensity of TNBC preclinical models. Eribulin induces mesenchymal-to-epithelial transition (MET) in primary TNBC in patients, but conventional chemotherapy does not. In the treatment-naive setting, but not after acquired resistance to other agents, eribulin sensitizes TNBC cells to subsequent treatment with other chemotherapeutics. These findings provide an epigenetic mechanism of action of eribulin, supporting its use early in the disease process for MET induction to prevent metastatic progression and chemoresistance. These findings warrant prospective clinical evaluation of the chemosensitizing effects of eribulin in the treatment-naive setting.


Asunto(s)
Antineoplásicos , Furanos , Cetonas , Policétidos Poliéteres , Neoplasias de la Mama Triple Negativas , Estados Unidos , Humanos , Neoplasias de la Mama Triple Negativas/patología , Ensamble y Desensamble de Cromatina , Estudios Prospectivos , Antineoplásicos/uso terapéutico
2.
Epigenomics ; 16(5): 293-308, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38356412

RESUMEN

Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options. Eribulin, a chemotherapeutic drug, induces epigenetic changes in cancer cells, suggesting a unique mechanism of action. Materials & methods: MDA-MB 231 cells were treated with eribulin and paclitaxel, and the samples from 53 patients treated with neoadjuvant eribulin were compared with those from 14 patients who received the standard-of-care treatment using immunohistochemistry. Results: Eribulin treatment caused significant DNA methylation changes in drug-tolerant persister TNBC cells, and it also elicited changes in the expression levels of epigenetic modifiers (DNMT1, TET1, DNMT3A/B) in vitro and in primary TNBC tumors. Conclusion: These findings provide new insights into eribulin's mechanism of action and potential biomarkers for predicting TNBC treatment response.


Asunto(s)
Metilación de ADN , Furanos , Policétidos Poliéteres , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Cetonas/farmacología , Cetonas/uso terapéutico , ADN/metabolismo , Línea Celular Tumoral , Oxigenasas de Función Mixta/genética , Proteínas Proto-Oncogénicas/genética
3.
bioRxiv ; 2023 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-37333096

RESUMEN

Triple-negative breast cancer (TNBC) is an aggressive disease subtype with limited treatment options. Eribulin is a chemotherapeutic approved for the treatment of advanced breast cancer that has been shown to elicit epigenetic changes. We investigated the effect of eribulin treatment on genome-scale DNA methylation patterns in TNBC cells. Following repeated treatment, The results showed that eribulin-induced changes in DNA methylation patterns evident in persister cells. Eribulin also affected the binding of transcription factors to genomic ZEB1 binding sites and regulated several cellular pathways, including ERBB and VEGF signaling and cell adhesion. Eribulin also altered the expression of epigenetic modifiers including DNMT1, TET1, and DNMT3A/B in persister cells. Data from primary human TNBC tumors supported these findings: DNMT1 and DNMT3A levels were altered by eribulin treatment in human primary TNBC tumors. Our results suggest that eribulin modulates DNA methylation patterns in TNBC cells by altering the expression of epigenetic modifiers. These findings have clinical implications for using eribulin as a therapeutic agent.

4.
bioRxiv ; 2023 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-37131809

RESUMEN

The epithelial-mesenchymal transition (EMT) is a developmental program co-opted by tumor cells that aids the initiation of the metastatic cascade. Tumor cells that undergo EMT are relatively chemoresistant, and there are currently no therapeutic avenues specifically targeting cells that have acquired mesenchymal traits. We show that treatment of mesenchymal-like triple-negative breast cancer (TNBC) cells with the microtubule-destabilizing chemotherapeutic eribulin, which is FDA-approved for the treatment of advanced breast cancer, leads to a mesenchymal-epithelial transition (MET). This MET is accompanied by loss of metastatic propensity and sensitization to subsequent treatment with other FDA-approved chemotherapeutics. We uncover a novel epigenetic mechanism of action that supports eribulin pretreatment as a path to MET induction that curtails metastatic progression and the evolution of therapy resistance.

6.
Dev Cell ; 55(5): 544-557.e6, 2020 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-33120014

RESUMEN

Differentiation therapy utilizes our understanding of the hierarchy of cellular systems to pharmacologically induce a shift toward terminal commitment. While this approach has been a paradigm in treating certain hematological malignancies, efforts to translate this success to solid tumors have met with limited success. Mammary-specific activation of PKA in mouse models leads to aberrant differentiation and diminished self-renewing potential of the basal compartment, which harbors mammary repopulating cells. PKA activation results in tumors that are more benign, exhibiting reduced metastatic propensity, loss of tumor-initiating potential, and increased sensitivity to chemotherapy. Analysis of tumor histopathology revealed features of overt differentiation with papillary characteristics. Longitudinal single-cell profiling at the hyperplasia and tumor stages uncovered an altered path of tumor evolution whereby PKA curtails the emergence of aggressive subpopulations. Acting through the repression of SOX4, PKA activation promotes tumor differentiation and represents a possible adjuvant to chemotherapy for certain breast cancers.


Asunto(s)
Diferenciación Celular , Autorrenovación de las Células , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Neoplasias Mamarias Animales/enzimología , Neoplasias Mamarias Animales/patología , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Linaje de la Célula , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Activación Enzimática , Femenino , Amplificación de Genes , Sitios Genéticos , Genoma Humano , Humanos , Neoplasias Mamarias Animales/genética , Ratones , Metástasis de la Neoplasia , Factores de Transcripción SOXC/metabolismo , Transducción de Señal
7.
Chem Commun (Camb) ; 53(100): 13352-13355, 2017 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-29192700

RESUMEN

Thera/NO - a small molecule that is activated by hydrogen peroxide to generate nitric oxide (NO) and a fluorescence signal is reported. Using cancer and primary cells, we show that Thera/NO preferentially releases NO in cancer cells, which can trigger DNA damage and cell death in them. The coupled fluorescence signal facilitated tracking the NO release in living cells without collateral consumption of NO.


Asunto(s)
Peróxido de Hidrógeno/química , Óxido Nítrico/biosíntesis , Bibliotecas de Moléculas Pequeñas/química , Muerte Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Fluorescencia , Células HeLa , Humanos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacología , Nanomedicina Teranóstica
8.
Chembiochem ; 18(15): 1529-1534, 2017 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-28470863

RESUMEN

Nitric oxide (NO) plays significant signalling roles in cells; the controlled generation of NO is of therapeutic relevance. Although a number of methods for the delivery and detection of NO are available, these events are typically mutually exclusive. Furthermore, the efficiency of delivery of NO can be compromised by detection technologies that consume NO. Here, we report FLUORO/NO, an esterase-activated diazeniumdiolate-based NO donor with an in-built fluorescence reporter. We demonstrate that this compound is capable of enhancing NO within cells in a dose-dependent manner, accompanied by a similar increase in fluorescence. The compatibility of this tool to study NO-mediated signalling as well as NO-mediated stress is demonstrated. FLUORO/NO is a convenient tool that shows NO-like activity and allows monitoring of NO release. This tool will help interrogate the redox biology of NO.


Asunto(s)
Cumarinas/farmacología , Donantes de Óxido Nítrico/farmacología , Triazenos/farmacología , Triazinas/farmacología , Umbeliferonas/farmacología , Carboxilesterasa/metabolismo , Cumarinas/síntesis química , Daño del ADN , Fluorescencia , Células HEK293 , Células HeLa , Humanos , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/síntesis química , Nitritos/análisis , Guanilil Ciclasa Soluble/metabolismo , Estereoisomerismo , Triazenos/síntesis química , Triazinas/síntesis química , Umbeliferonas/síntesis química , Valeratos/metabolismo
9.
Biochim Biophys Acta Mol Cell Res ; 1864(1): 177-190, 2017 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-27845209

RESUMEN

Cellular senescence is an outcome of the accumulation of DNA damage which induces the growth arrest in cells. Physiologically, it is presumed to be mediated by accumulation of reactive oxygen species (ROS). Here, we show that another free radical, nitric oxide (NO) produced during inflammation or present as an environmental pollutant can also induce cellular senescence. In primary cells and various immortalized cell lines, exposure to chronic NO, through external addition or internally generated by iNOS expression, leads to the activation of DNA damage response and causes cellular senescence. The phenotype generated by NO includes robust growth arrest, increase in the levels of the DNA damage foci, ROS, SAß-gal staining, and inflammatory cytokines like IL-6 and IL-8, all hallmarks of cellular senescence similar to replicative senescence. Mechanistically, inhibitor and knockdown analysis revealed that NO mediates senescence through ATM kinase activation and the viability of cells is dependent on both ROS and ATM kinase involving the ATM-ROS-iNOS axis. Overall, we demonstrate that nitric oxide mediates cellular senescence through a novel free radical dependent genotoxic stress pathway.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Senescencia Celular/genética , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Daño del ADN , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Células HeLa , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitroprusiato/farmacología , Transducción de Señal
10.
J Cell Sci ; 128(2): 342-53, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25416819

RESUMEN

Cells exposed to genotoxic stress induce cellular senescence through a DNA damage response (DDR) pathway regulated by ATM kinase and reactive oxygen species (ROS). Here, we show that the regulatory roles for ATM kinase and ROS differ during induction and maintenance of cellular senescence. Cells treated with different genotoxic agents were analyzed using specific pathway markers and inhibitors to determine that ATM kinase activation is directly proportional to the dose of the genotoxic stress and that senescence initiation is not dependent on ROS or the p53 status of cells. Cells in which ROS was quenched still activated ATM and initiated the DDR when insulted, and progressed normally to senescence. By contrast, maintenance of a viable senescent state required the presence of ROS as well as activated ATM. Inhibition or removal of either of the components caused cell death in senescent cells, through a deregulated ATM-ROS axis. Overall, our work demonstrates existence of an intricate temporal hierarchy between genotoxic stress, DDR and ROS in cellular senescence. Our model reports the existence of different stages of cellular senescence with distinct regulatory networks.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Senescencia Celular/genética , Daño del ADN/genética , Especies Reactivas de Oxígeno/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Bromodesoxiuridina/administración & dosificación , Regulación de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética
11.
Int J Nanomedicine ; 8: 2943-60, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23966782

RESUMEN

BACKGROUND: [Corrected] Muscular dystrophies consist of a number of juvenile and adult forms of complex disorders which generally cause weakness or efficiency defects affecting skeletal muscles or, in some kinds, other types of tissues in all parts of the body are vastly affected. In previous studies, it was observed that along with muscular dystrophy, immune inflammation was caused by inflammatory cells invasion - like T lymphocyte markers (CD8+/CD4+). Inflammatory processes play a major part in muscular fibrosis in muscular dystrophy patients. Additionally, a significant decrease in amounts of two myogenic recovery factors (myogenic differentation 1 [MyoD] and myogenin) in animal models was observed. The drug glatiramer acetate causes anti-inflammatory cytokines to increase and T helper (Th) cells to induce, in an as yet unknown mechanism. MyoD recovery activity in muscular cells justifies using it alongside this drug. METHODS: In this study, a nanolipodendrosome carrier as a drug delivery system was designed. The purpose of the system was to maximize the delivery and efficiency of the two drug factors, MyoD and myogenin, and introduce them as novel therapeutic agents in muscular dystrophy phenotypic mice. The generation of new muscular cells was analyzed in SW1 mice. Then, immune system changes and probable side effects after injecting the nanodrug formulations were investigated. RESULTS: The loaded lipodendrimer nanocarrier with the candidate drug, in comparison with the nandrolone control drug, caused a significant increase in muscular mass, a reduction in CD4+/CD8+ inflammation markers, and no significant toxicity was observed. The results support the hypothesis that the nanolipodendrimer containing the two candidate drugs will probably be an efficient means to ameliorate muscular degeneration, and warrants further investigation.


Asunto(s)
Liposomas/uso terapéutico , Distrofias Musculares/tratamiento farmacológico , Proteína MioD/uso terapéutico , Nanopartículas/uso terapéutico , Péptidos/uso terapéutico , Animales , Peso Corporal/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Acetato de Glatiramer , Liposomas/química , Masculino , Ratones , Microscopía Electrónica de Transmisión , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Proteína MioD/química , Proteína MioD/farmacología , Nandrolona/farmacología , Nanopartículas/química , Tamaño de la Partícula , Péptidos/química , Péptidos/farmacología
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