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1.
Nature ; 538(7626): 477-482, 2016 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-27760111

RESUMEN

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Modelos Biológicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Tiofenos/farmacología , Tiofenos/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Leucemia/tratamiento farmacológico , Leucemia/metabolismo , Leucemia/patología , Linfoma/tratamiento farmacológico , Linfoma/metabolismo , Linfoma/patología , Masculino , Ratones , Modelos Moleculares , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/química , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neoplasias/metabolismo , Pirimidinas/administración & dosificación , Tiofenos/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismo
2.
Cancers (Basel) ; 12(6)2020 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-32517171

RESUMEN

Background: Focal amplification of fibroblast growth factor receptor 1 (FGFR1) defines a subgroup of breast cancers with poor prognosis and high risk of recurrence. We sought to demonstrate the potential of circulating cell-free DNA (cfDNA) analysis to evaluate FGFR1 copy numbers from a cohort of 100 metastatic breast cancer (mBC) patients. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples were screened for FGFR1 amplification by FISH, and positive cases were confirmed with a microarray platform (OncoscanTM). Subsequently, cfDNA was evaluated by two approaches, i.e., mFAST-SeqS and shallow whole-genome sequencing (sWGS), to estimate the circulating tumor DNA (ctDNA) allele fraction (AF) and to evaluate the FGFR1 status. Results: Tissue-based analyses identified FGFR1 amplifications in 20/100 tumors. All cases with a ctDNA AF above 3% (n = 12) showed concordance for FGFR1 status between tissue and cfDNA. In one case, we were able to detect a high-level FGFR1 amplification, although the ctDNA AF was below 1%. Furthermore, high levels of ctDNA indicated an association with unfavorable prognosis based on overall survival. Conclusions: Screening for FGFR1 amplification in ctDNA might represent a viable strategy to identify patients eligible for treatment by FGFR inhibition, and mBC ctDNA levels might be used for the evaluation of prognosis in clinical drug trials.

3.
Neurosci Res ; 70(4): 349-60, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21609738

RESUMEN

To improve our understanding of the molecular events underlying the effects of positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (S)-AMPA-type glutamate receptors, gene expression profiles of primary cortical culture were measured by Agilent-Microarray technique under (S)-AMPA (1µM) stimulation for 0.5, 6, 24 and 48h in the presence or absence of S70340 (30µM), an allosteric potentiator of AMPA receptors. (S)-AMPA and S70340 treatment alone have little effect on gene expression whereas as early as 6h, their combination induced a large number of genes known to decrease apoptosis and mediate cell survival. Pathway analyses of (S)-AMPA+S70340 treatment-mediated gene expression from 6 to 48h further suggested the activation of cellular functions including neuron differentiation and neurite outgrowth. A proportion of genes implicated in these functions encode proteins involved in environmental cues and are expressed in growth cones, such as extracellular matrix component proteins and filopodia microfilament-associated proteins. Time course analysis of mRNA expression combined with in silico promoter analysis revealed an enrichment in the cAMP response element (CRE) among co-regulated genes. This study demonstrated that S70340-mediated AMPA potentialisation activated genes and functional processes involved in neuroprotective and cognitive effects and describes putative new functional biomarkers.


Asunto(s)
Corteza Cerebral/fisiología , Perfilación de la Expresión Génica/métodos , Estudio de Asociación del Genoma Completo/métodos , Receptores AMPA/agonistas , Receptores AMPA/fisiología , Animales , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Redes Reguladoras de Genes/genética , Ratas , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/análogos & derivados , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiónico/farmacología
4.
PPAR Res ; 20102010.
Artículo en Inglés | MEDLINE | ID: mdl-20953342

RESUMEN

Rosiglitazone (RSG), developed for the treatment of type 2 diabetes mellitus, is known to have potent effects on carbohydrate and lipid metabolism leading to the improvement of insulin sensitivity in target tissues. To further assess the capacity of RSG to normalize gene expression in insulin-sensitive tissues, we compared groups of 18-day-treated db/db mice with increasing oral doses of RSG (10, 30, and 100 mg/kg/d) with untreated non-diabetic littermates (db/+). For this aim, transcriptional changes were measured in liver, inguinal adipose tissue (IAT) and soleus muscle using microarrays and real-time PCR. In parallel, targeted metabolomic assessment of lipids (triglycerides (TGs) and free fatty acids (FFAs)) in plasma and tissues was performed by UPLC-MS methods. Multivariate analyses revealed a relationship between the differential gene expressions in liver and liver trioleate content and between blood glucose levels and a combination of differentially expressed genes measured in liver, IAT, and muscle. In summary, we have integrated gene expression and targeted metabolomic data to present a comprehensive overview of RSG-induced changes in a diabetes mouse model and improved the molecular understanding of how RSG ameliorates diabetes through its effect on the major insulin-sensitive tissues.

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