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1.
Clin. transl. oncol. (Print) ; 24(11): 2120-2135, noviembre 2022.
Artigo em Inglês | IBECS | ID: ibc-210140

RESUMO

Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin–proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins.MethodsWe performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts.ResultsWe uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C.ConclusionsOur study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer. (AU)


Assuntos
Humanos , Aminopiridinas , Benzimidazóis , Neoplasias da Mama/patologia , Hormônios/uso terapêutico , Fosfatidilinositol 3-Quinases , Ubiquitinas/uso terapêutico , Purinas , RNA Mensageiro
2.
Clin. transl. oncol. (Print) ; 24(11): 2231-2240, noviembre 2022. graf
Artigo em Inglês | IBECS | ID: ibc-210151

RESUMO

Although lorlatinib, the third generation of echinoderm microtubule protein 4-anaplastic lymphoma kinase (EML4-ALK) tyrosine kinase inhibitor (TKI), overcame the previous generation ALK-TKIs’ drug resistance problems, but the mechanism of lorlatinib resistance remained unclear. Furthermore, optimal chemotherapy for lorlatinib-resistant non-small cell lung cancer (NSCLC) patients was still unknown.MethodsA lorlatinib-resistant NSCLC cell line SNU-2535LR was generated by gradually increasing dose of lorlatinib to crizotinib-resistant cell line SNU-2535 in vitro. To study the resistance mechanism of SNU-2535LR cells, we applied CCK-8 assay to detect the sensitivity of crizotinib and the reverse effect of APR-246, a p53 activator, on lorlatinib-induced resistance and different chemotherapy drugs to SNU-2535LR cells. We also detected the expressions of EML4-ALK-related proteins of SNU-2535LR cells via western blot.Please confirm that author names have been identified correctly and are presented in the right order. (AU)


Assuntos
Humanos , Aminopiridinas , Cisplatino/uso terapêutico , Crizotinibe/uso terapêutico , Docetaxel/uso terapêutico , Resistência a Medicamentos , Paclitaxel/uso terapêutico , Pirazóis , Sincalida , Mutação
3.
Clin. transl. oncol. (Print) ; 24(11): 2251-2253, noviembre 2022.
Artigo em Inglês | IBECS | ID: ibc-210154

RESUMO

Purpose Despite signifcant improvement in therapeuticdevelopment in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormonepositive subtype (HR(+)) (also known as luminal type) is themost prevalant category of breast cancer, comprising~70%of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the propertiesof CDK4/6 inhibitors extend beyond inhibition of the cellcycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinomerewiring, modulation of the proteosome, and many others.The ubiquitin–proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis andturnover of proteins.Methods We performed transcriptional profiling of theHR(+) breast cancer cell lines MCF7 and T47D treated withPalbociclib. Diferential expressed genes were analyzed fornovel pathways enriched. The results were further validatedwith biochemical assays and with real world clinical database cohorts.Results We uncovered a novel mechanism that demonstratethe CDK4/6 inhibitors suppress the expression of threeubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T.Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNAand protein level, but this phenomenon was not shared withabemaciclib. These three E2 enzymes modulate severalE3 ubiquitin ligases, including the APC/C complex whichplays a role in G1/S progression. We further demonstrate theUBE2C/UBE2T expression levels are associated with breastcancer survival, and HR(+) breast cancer cells demonstratedependence on the UBE2C.Conclusions Our study suggests a novel link betweenCDK4/6 inhibitor and UPP pathway, adding to the potentialmechanisms of their clinical efcacy in cancer. (AU)


Assuntos
Humanos , Aminopiridinas , Benzimidazóis , Neoplasias da Mama/patologia , Hormônios/uso terapêutico , Fosfatidilinositol 3-Quinases , Ubiquitinas/uso terapêutico , Purinas , RNA Mensageiro
4.
Arch. bronconeumol. (Ed. impr.) ; 54(12): 614-618, dic. 2018. graf, tab
Artigo em Inglês | IBECS | ID: ibc-174927

RESUMO

Background: The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs. Methods: We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real-life in Spain. 20 CF patients were included, all aged 6 and upwards and presented with ppFEV1 < 40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125 mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months. Results: The mean age was 26.65 (range of 10-45), while the mean ppFEV1 before the treatment was 32.4% and mean BMI was 19.9 kg/m2. We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor/ivacaftor, but no differences were found. However, a moderate association between days of intravenous antibiotic needed and the use of lumacaftor/ivacaftor (p = 0.001) was established. Indeed, under the lumacaftor/ivacaftor, patients required 5.8 days of intravenous antibiotic treatment compared to 14.9 days prior to study. Also, severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor/ivacaftor treatment (p = 0.003). Finally, 75% of the sample presented with AEs, which led 35% of the subjects to discontinue the treatment. Conclusions: While treatment with lumacaftor/ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations, no improvement in ppFEV1 or BMI was found


Introducción: La mutación causante de fibrosis quística (FQ) más frecuente es la deltaF508 (F508del), presente en el 28% de los pacientes españoles con FQ. Aunque la literatura sobre estudios en vida real en pacientes de FQ homocigotos para F508del tratados con lumacaftor/ivacaftor es escasa, pone de manifiesto la necesidad de contar con mejores estrategias para prevenir los efectos adversos (EA) relacionados con el tratamiento, así como del desarrollo de nuevos fármacos. Métodos: Se realizó un estudio observacional, retrospectivo multicéntrico para describir los efectos del tratamiento con lumacaftor/ivacaftor en vida real en España. Se incluyeron 20 pacientes con FQ, edad superior a los 6 años y ppFEV1 < 40%, procedentes de unidades de FQ de todo el país. Para los fines del estudio, fueron tratados con 2 comprimidos de lumacaftor/ivacaftor 200/125 mg/2 veces al día como parte de un programa de uso compasivo a lo largo de 2016. El criterio de valoración primario se midió en las muestras de todos los pacientes. Los datos de ppFEV1 se analizaron al inicio y cada 6 meses. Resultados: La mediana de edad fue de 26,65 (rango: 10-45), mientras que la mediana de ppFEV1 antes del tratamiento fue del 32,4% y la mediana del IMC 19,9 kg/m2. No se encontraron diferencias al analizar los cambios de ppVEF1 e IMC desde el inicio y durante el tratamiento con lumacaftor/ivacaftor. Sin embargo, se estableció una asociación moderada entre los días requeridos de antibiótico intravenoso y el uso de lumacaftor/ivacaftor (p = 0,001). De hecho, con lumacaftor/ivacaftor, los pacientes requirieron 5,8 días de tratamiento intravenoso con antibiótico, comparado con los 14,9 días previos al estudio. Además, el número de exacerbaciones pulmonares graves que requirieron hospitalización fue estadísticamente menor con lumacaftor/ivacaftor (p = 0,003). Por último, el 75% de la muestra presentó EA, lo cual supuso la discontinuación del tratamiento en un 35% de los casos. Conclusión: El tratamiento con lumacaftor/ivacaftor mejoró el número de exacerbaciones pulmonares severas, pero no supuso mejora ni en el ppFEV1 ni el IMC


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Fibrose Cística/tratamento farmacológico , Aminofenóis/administração & dosagem , Aminopiridinas/administração & dosagem , Combinação de Medicamentos , Resultado do Tratamento , Estudos Retrospectivos , Estudo Observacional
5.
Rev. clín. esp. (Ed. impr.) ; 211(supl.2): 22-30, mar. 2011. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-148576

RESUMO

La enfermedad pulmonar obstructiva crónica (EPOC) es un término que engloba un grupo de trastornos caracterizados por la presencia de obstrucción crónica de las vías aéreas. Este amplio paraguas diagnóstico incluye varios fenotipos clínicos que se solapan y que responden de forma diferente a cada tipo de intervención terapéutica. Roflumilast es un fármaco perteneciente a la nueva clase terapéutica de los inhibidores de la fosfodiesterasa 4 (PDE4). Se puede considerar el primer fármaco desarrollado para el tratamiento de un fenotipo específico de la EPOC (EPOC asociada a bronquitis crónica). En modelos preclínicos, roflumilast ha mostrado una potente acción antiinflamatoria sobre una amplia variedad de células y mediadores inflamatorios, así como sobre otros mecanismos etiopatogénicos propios de la EPOC. El presente documento revisa la evidencia generada durante el desarrollo clínico de roflumilast , con un énfasis especial en los estudios que valoran el fármaco en el contexto similar a nuestra práctica clínica habitual (AU)


Chronic obstructive pulmonary disease (COPD) encompasses a group of diseases characterized by chronic airway obstruction. This broad diagnostic umbrella includes several clinical phenotypes that overlap and respond differently to each type of therapeutic intervent ion. Roflumilast is a drug belonging to the new therapeutic class of phosphyldiesterase-4 (PDE4) inhibitors and can be considered the first drug to be developed for a specific COPD phenotype (COPD associated with chronic bronchit is). In preclinical models, roflumilast has shown potent ant iinflammatory action against a wide variety of cells and inflammatory mediators, as well as against the etiopathogenic mechanisms of COPD. The present article reviews the evidence generated during the clinical development of roflumilast , with special emphasis on studies evaluating the drug in a context similar to that of routine clinical pract ice (AU)


Assuntos
Humanos , Aminopiridinas/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Benzamidas/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Ciclopropanos/uso terapêutico , Quimioterapia Combinada , Derivados da Escopolamina/uso terapêutico
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