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Métodos Terapéuticos y Terapias MTCI
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1.
FASEB J ; 34(9): 11860-11882, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32652772

RESUMEN

Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/farmacología , Tigeciclina/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Ratones SCID , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Recurrencia Local de Neoplasia/prevención & control , Inhibidores de la Síntesis de la Proteína/farmacología
2.
Hepatology ; 69(1): 376-393, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30033593

RESUMEN

Therapeutic options for patients with advanced-stage hepatocellular carcinoma (HCC) are very limited. The only approved first-line treatment is the multi-tyrosine kinase inhibitor sorafenib, which shows low response rates and severe side effects. In particular, the compensatory activation of growth factor receptors leads to chemoresistance and limits the clinical impact of sorafenib. However, combination approaches to improve sorafenib have failed. Here we investigate the inhibition of cyclin-dependent kinase 5 (Cdk5) as a promising combination strategy to improve sorafenib response in HCC. Combination of sorafenib with Cdk5 inhibition (genetic knockdown by short hairpin RNA or CRISPR/Cas9 and pharmacologic inhibition) synergistically impaired HCC progression in vitro and in vivo by inhibiting both tumor cell proliferation and migration. Importantly, these effects were mediated by a mechanism for Cdk5: A liquid chromatography-tandem mass spectrometry-based proteomic approach revealed that Cdk5 inhibition interferes with intracellular trafficking, a process crucial for cellular homeostasis and growth factor receptor signaling. Cdk5 inhibition resulted in an accumulation of enlarged vesicles and respective cargos in the perinuclear region, considerably impairing the extent and quality of growth factor receptor signaling. Thereby, Cdk5 inhibition offers a comprehensive approach to globally disturb growth factor receptor signaling that is superior to specific inhibition of individual growth factor receptors. Conclusion: Cdk5 inhibition represents an effective approach to improve sorafenib response and to prevent sorafenib treatment escape in HCC. Notably, Cdk5 is an addressable target frequently overexpressed in HCC, and with Dinaciclib, a clinically tested Cdk5 inhibitor is readily available. Thus, our study provides evidence for clinically evaluating the combination of sorafenib and Dinaciclib to improve the therapeutic situation for patients with advanced-stage HCC.


Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Quinasa 5 Dependiente de la Ciclina/antagonistas & inhibidores , Neoplasias Hepáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib/uso terapéutico , Animales , Femenino , Humanos , Ratones , Resultado del Tratamiento , Células Tumorales Cultivadas
3.
Berl Munch Tierarztl Wochenschr ; 119(1-2): 7-16, 2006.
Artículo en Alemán | MEDLINE | ID: mdl-16450702

RESUMEN

Improvements of animal health, welfare and product quality are major goals of modern animal breeding. Thus, in addition to the classical production traits, functional traits such as disease resistance, fertility and longevity moved into the center of animal breeder's interests. Due to their low heritability, the improvement of functional traits using conventional approaches of phenotypic testing and quantitative genetics is difficult. A number of studies have been conducted worldwide in various species to map quantitative trait loci (QTLs) and to identify genetic markers for health traits. This has revealed a plethora of chromosome regions which may harbor genes with relevance for animal health. Functional genome research integrates holistic investigations at the level of the genome, at the level of gene activity (transcriptome, proteome) and at various levels of phenotypic expression. The integration of all these levels of information provides the basis for the functional dissection of complex traits. This review provides an overview of the most important strategies for holistic transcriptome and proteome analyses. The successful application of these techniques is exemplified by our studies of bovine reproductive biology.


Asunto(s)
Bovinos/genética , Bovinos/fisiología , Proteómica , Sitios de Carácter Cuantitativo , Reproducción/fisiología , Animales , Mapeo Cromosómico , Femenino , Perfilación de la Expresión Génica/veterinaria , Regulación de la Expresión Génica , Marcadores Genéticos , Genoma , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos/veterinaria , Proteoma , Reproducción/genética
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