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1.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800359

RESUMEN

Plasminogen activator inhibitor-1 (PAI-1) is the main physiological inhibitor of plasminogen activators (PAs) and is therefore an important inhibitor of the plasminogen/plasmin system. Being the fast-acting inhibitor of tissue-type PA (tPA), PAI-1 primarily attenuates fibrinolysis. Through inhibition of urokinase-type PA (uPA) and interaction with biological ligands such as vitronectin and cell-surface receptors, the function of PAI-1 extends to pericellular proteolysis, tissue remodeling and other processes including cell migration. This review aims at providing a general overview of the properties of PAI-1 and the role it plays in many biological processes and touches upon the possible use of PAI-1 inhibitors as therapeutics.


Asunto(s)
Enfermedades Cardiovasculares , Movimiento Celular/inmunología , Fibrinólisis/inmunología , Proteínas de Neoplasias , Neoplasias , Inhibidor 1 de Activador Plasminogénico , Proteolisis , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Fibrosis , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/inmunología , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Neoplasias/patología , Inhibidor 1 de Activador Plasminogénico/inmunología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/inmunología , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo
2.
Int J Mol Sci ; 22(6)2021 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-33802080

RESUMEN

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.


Asunto(s)
Quinasas Ciclina-Dependientes , Proteínas de Neoplasias , Neoplasias , Enfermedades Neurodegenerativas , Inhibidores de Proteínas Quinasas , Sitios de Unión , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Quinasas Ciclina-Dependientes/química , Quinasas Ciclina-Dependientes/metabolismo , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/enzimología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad
3.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805602

RESUMEN

Carriers of genetic material are divided into vectors of viral and non-viral origin. Viral carriers are already successfully used in experimental gene therapies, but despite advantages such as their high transfection efficiency and the wide knowledge of their practical potential, the remaining disadvantages, namely, their low capacity and complex manufacturing process, based on biological systems, are major limitations prior to their broad implementation in the clinical setting. The application of non-viral carriers in gene therapy is one of the available approaches. Poly(amidoamine) (PAMAM) dendrimers are repetitively branched, three-dimensional molecules, made of amide and amine subunits, possessing unique physiochemical properties. Surface and internal modifications improve their physicochemical properties, enabling the increase in cellular specificity and transfection efficiency and a reduction in cytotoxicity toward healthy cells. During the last 10 years of research on PAMAM dendrimers, three modification strategies have commonly been used: (1) surface modification with functional groups; (2) hybrid vector formation; (3) creation of supramolecular self-assemblies. This review describes and summarizes recent studies exploring the development of PAMAM dendrimers in anticancer gene therapies, evaluating the advantages and disadvantages of the modification approaches and the nanomedicine regulatory issues preventing their translation into the clinical setting, and highlighting important areas for further development and possible steps that seem promising in terms of development of PAMAM as a carrier of genetic material.


Asunto(s)
Dendrímeros/síntesis química , Regulación Neoplásica de la Expresión Génica , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Proteínas de Neoplasias/antagonistas & inhibidores , Neoplasias/terapia , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/síntesis química , Dendrímeros/administración & dosificación , Regulación Gubernamental , Humanos , MicroARNs/administración & dosificación , MicroARNs/genética , MicroARNs/metabolismo , Nanomedicina/legislación & jurisprudencia , Nanomedicina/métodos , Nanopartículas/administración & dosificación , Nanopartículas/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/metabolismo , Plásmidos/administración & dosificación , Plásmidos/química , Plásmidos/metabolismo , ARN Mensajero/administración & dosificación , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Propiedades de Superficie
4.
BMC Cancer ; 21(1): 208, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33648453

RESUMEN

BACKGROUND: Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). METHODS: This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. RESULTS: In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75-91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5-19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2-not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. CONCLUSION: Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. TRIAL REGISTRATION: The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).


Asunto(s)
Afatinib/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Afatinib/administración & dosificación , Afatinib/efectos adversos , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Relación Dosis-Respuesta a Droga , Receptores ErbB/antagonistas & inhibidores , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/epidemiología , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Enfermedades de la Piel/inducido químicamente
5.
BMC Cancer ; 21(1): 207, 2021 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-33648461

RESUMEN

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide; it is the fourth leading cause of death in the world and the third in Brazil. Mutations in the APC, DCC, KRAS and TP53 genes have been associated with the progression of sporadic CRC, occurring at defined pathological stages of the tumor progression and consequently modulating several genes in the corresponding signaling pathways. Therefore, the identification of gene signatures that occur at each stage during the CRC progression is critical and can present an impact on the diagnosis and prognosis of the patient. In this study, our main goal was to determine these signatures, by evaluating the gene expression of paired colorectal adenoma and adenocarcinoma samples to identify novel genetic markers in association to the adenoma-adenocarcinoma stage transition. METHODS: Ten paired adenoma and adenocarcinoma colorectal samples were subjected to microarray gene expression analysis. In addition, mutations in APC, KRAS and TP53 genes were investigated by DNA sequencing in paired samples of adenoma, adenocarcinoma, normal tissue, and peripheral blood from ten patients. RESULTS: Gene expression analysis revealed a signature of 689 differentially expressed genes (DEG) (fold-change> 2, p< 0.05), between the adenoma and adenocarcinoma paired samples analyzed. Gene pathway analysis using the 689 DEG identified important cancer pathways such as remodeling of the extracellular matrix and epithelial-mesenchymal transition. Among these DEG, the ETV4 stood out as one of the most expressed in the adenocarcinoma samples, further confirmed in the adenocarcinoma set of samples from the TCGA database. Subsequent in vitro siRNA assays against ETV4 resulted in the decrease of cell proliferation, colony formation and cell migration in the HT29 and SW480 colorectal cell lines. DNA sequencing analysis revealed KRAS and TP53 gene pathogenic mutations, exclusively in the adenocarcinomas samples. CONCLUSION: Our study identified a set of genes with high potential to be used as biomarkers in CRC, with a special emphasis on the ETV4 gene, which demonstrated involvement in proliferation and migration.


Asunto(s)
Adenocarcinoma/genética , Adenoma/genética , Neoplasias Colorrectales/genética , Genes Relacionados con las Neoplasias , Proteínas de Neoplasias/fisiología , Proteínas Proto-Oncogénicas c-ets/fisiología , Adenocarcinoma/química , Adenocarcinoma/patología , Adenoma/química , Adenoma/patología , Anciano , Biomarcadores de Tumor/genética , Brasil , División Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/química , Neoplasias Colorrectales/patología , ADN de Neoplasias/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Ontología de Genes , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-ets/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ets/genética , Interferencia de ARN , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/farmacología , Análisis de Matrices Tisulares , Transcriptoma , Ensayo de Tumor de Célula Madre
6.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673346

RESUMEN

2-Methoxyestradiol (2-ME2) possesses anti-tumorigenic activities in multiple tumor models with acceptable tolerability profile in humans. Incomplete understanding of the mechanism has hindered its development as an anti-tumorigenic compound. We have identified for the first-time macrophage stimulatory protein 1 receptor (MST1R) as a potential target of 2-ME2 in prostate cancer cells. Human tissue validation studies show that MST1R (a.k.a RON) protein levels are significantly elevated in prostate cancer tissues compared to adjacent normal/benign glands. Serum levels of macrophage stimulatory protein (MSP), a ligand for RON, is not only associated with the risk of disease recurrence, but also significantly elevated in samples from African American patients. 2-ME2 treatment inhibited mechanical properties such as adhesion and elasticity that are associated with epithelial mesenchymal transition by downregulating mRNA expression and protein levels of MST1R in prostate cancer cell lines. Intervention with 2-ME2 significantly reduced tumor burden in mice. Notably, global metabolomic profiling studies identified significantly higher circulating levels of bile acids in castrated animals that were decreased with 2-ME2 intervention. In summary, findings presented in this manuscript identified MSP as a potential marker for predicting biochemical recurrence and suggest repurposing 2-ME2 to target RON signaling may be a potential therapeutic modality for prostate cancer.


Asunto(s)
2-Metoxiestradiol/farmacología , Reposicionamiento de Medicamentos , Proteínas de Neoplasias , Neoplasias de la Próstata , Proteínas Tirosina Quinasas Receptoras , Animales , Humanos , Masculino , Ratones , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Células PC-3 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo
7.
Cancer Sci ; 112(5): 1987-1996, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-33686706

RESUMEN

Signaling pathways that drive bladder cancer (BC) progression may be promising and specific targets for systemic therapy. Here, we investigated the clinical significance and targetability of NOTCH and mitogen-activated protein kinase (MAPK) signaling for this aggressive malignancy. We assessed NOTCH1 and MAPK activity in 222 stage III and IV BC specimens of patients that had undergone radical cystectomy, and tested for clinical associations including cancer-specific and overall survival. We examined therapeutic effects of NOTCH and MAPK repression in a murine xenograft model of human bladder cancer cells and evaluated tumor growth and tumor cell plasticity. In BC, NOTCH1 and MAPK signaling marked two distinct tumor cell subpopulations. The combination of high NOTCH1 and high MAPK activity indicated poor cancer-specific and overall survival in univariate and multivariate analyses. Inhibition of NOTCH and MAPK in BC xenografts in vivo depleted targeted tumor cell subpopulations and revealed strong plasticity in signaling pathway activity. Combinatorial inhibition of NOTCH and MAPK signaling most strongly suppressed tumor growth. Our findings indicate that tumor cell subpopulations with high NOTCH and MAPK activity both contribute to tumor progression. Furthermore, we propose a new concept for BC therapy, which advocates specific and simultaneous targeting of these different tumor cell subpopulations through combined NOTCH and MAPK inhibition.


Asunto(s)
Proteínas Quinasas Activadas por Mitógenos/metabolismo , Receptor Notch1/metabolismo , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Anciano , Análisis de Varianza , Animales , Bencimidazoles/uso terapéutico , Línea Celular Tumoral , Dibenzazepinas/uso terapéutico , Progresión de la Enfermedad , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Ratones , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Pronóstico , Receptor Notch1/antagonistas & inhibidores , Análisis de Regresión , Transducción de Señal , Análisis de Matrices Tisulares/métodos , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Int J Mol Sci ; 22(4)2021 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-33670397

RESUMEN

Even though cervical cancer is partly preventable, it still poses a great public health problem throughout the world. Current therapies have vastly improved the clinical outcomes of cervical cancer patients, but progress in new systemic treatment modalities has been slow in the last years. Especially for patients with advanced disease this is discouraging, as their prognosis remains very poor. The pathogen-induced nature, the considerable mutational load, the involvement of genes regulating the immune response, and the high grade of immune infiltration, suggest that immunotherapy might be a promising strategy to treat cervical cancer. In this literature review, we focus on the use of PD-1 blocking therapy in cervical cancer, pembrolizumab in particular, as it is the only approved immunotherapy for this disease. We discuss why it has great clinical potential, how it opens doors for personalized treatment in cervical cancer, and which trials are aiming to expand its clinical use.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia , Proteínas de Neoplasias/antagonistas & inhibidores , Recurrencia Local de Neoplasia/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Neoplasias del Cuello Uterino/terapia , Femenino , Humanos , Metástasis de la Neoplasia , Proteínas de Neoplasias/inmunología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Receptor de Muerte Celular Programada 1/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología
9.
Adv Protein Chem Struct Biol ; 124: 23-46, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33632467

RESUMEN

CK2 is a constitutively active Ser/Thr protein kinase which phosphorylates hundreds of substrates. Since they are primarily related to survival and proliferation pathways, the best-known pathological roles of CK2 are in cancer, where its targeting is currently being considered as a possible therapy. However, CK2 activity has been found instrumental in many other human pathologies, and its inhibition will expectably be extended to different purposes in the near future. Here, after a description of CK2 features and implications in diseases, we analyze the different inhibitors and strategies available to target CK2, and update the results so far obtained by their in vivo application.


Asunto(s)
Quinasa de la Caseína II , Sistemas de Liberación de Medicamentos , Proteínas de Neoplasias , Neoplasias , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/metabolismo , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología
10.
Adv Protein Chem Struct Biol ; 124: 311-336, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33632469

RESUMEN

Receptor tyrosine kinases (RTKs) are important drug targets for cancer and immunological disorders. Crystal structures of individual RTK domains have contributed greatly to the structure-based drug design of clinically used drugs. Low-resolution structures from electron microscopy are now available for the RTKs, EGFR, PDGFR, and Kit. However, there are still no high-resolution structures of full-length RTKs due to the technical challenges of working with these complex, membrane proteins. Here, we review what has been learned from structural studies of these three RTKs regarding their mechanisms of ligand binding, activation, oligomerization, and inhibition. We discuss the implications for drug design. More structural data on full-length RTKs may facilitate the discovery of druggable sites and drugs with improved specificity and effectiveness against resistant mutants.


Asunto(s)
Antineoplásicos , Diseño de Fármacos , Enfermedades del Sistema Inmune , Proteínas de Neoplasias , Neoplasias , Inhibidores de Proteínas Quinasas , Proteínas Tirosina Quinasas Receptoras , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Enfermedades del Sistema Inmune/enzimología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo
11.
BMC Cancer ; 21(1): 200, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33637083

RESUMEN

BACKGROUND: Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS: We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS: Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS: Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas de Neoplasias/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/prevención & control , Carcinoma Ductal Pancreático/secundario , Adhesión Celular/efectos de los fármacos , Agregación Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Autorrenovación de las Células/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacología , Sinergismo Farmacológico , Femenino , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Células Madre Neoplásicas/patología , Tamaño de los Órganos/efectos de los fármacos , Neoplasias Pancreáticas/patología , Neoplasias Peritoneales/prevención & control , Neoplasias Peritoneales/secundario , Peritoneo/efectos de los fármacos , Peritoneo/metabolismo , Peritoneo/patología , Peritonitis/tratamiento farmacológico , Peritonitis/patología
12.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540837

RESUMEN

In almost all cases, hepatocellular carcinoma (HCC) develops as the endpoint of a sequence that starts with chronic liver injury, progresses to liver cirrhosis, and finally, over years and decades, results in liver cancer. Recently, the role of non-coding RNA such as microRNA (miRNA) has been demonstrated in the context of chronic liver diseases and HCC. Moreover, data from a phase II trial suggested a potential role of microRNAs as therapeutics in hepatitis-C-virus infection, representing a significant risk factor for development of liver cirrhosis and HCC. Despite progress in the clinical management of chronic liver diseases, pharmacological treatment options for patients with liver cirrhosis and/or advanced HCC are still limited. With their potential to regulate whole networks of genes, miRNA might be used as novel therapeutics in these patients but could also serve as biomarkers for improved patient stratification. In this review, we discuss available data on the role of miRNA in the transition from liver cirrhosis to HCC. We highlight opportunities for clinical translation and discuss open issues applicable to future developments.


Asunto(s)
Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Cirrosis Hepática/genética , Neoplasias Hepáticas/genética , MicroARNs/genética , ARN Neoplásico/genética , Animales , Antineoplásicos/uso terapéutico , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/terapia , Transformación Celular Neoplásica , Ensayos Clínicos como Asunto , Regulación Neoplásica de la Expresión Génica , Hepatitis Crónica/complicaciones , Hepatitis Crónica/genética , Humanos , Inmunoterapia , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/terapia , Ratones , MicroARNs/uso terapéutico , Proteínas de Neoplasias/antagonistas & inhibidores , Oligonucleótidos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
13.
Molecules ; 26(4)2021 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546391

RESUMEN

Herein, the activity of adamantanyl-tethered-biphenyl amines (ATBAs) as oestrogen receptor alpha (ERα) modulating ligands is reported. Using an ERα competitor assay it was demonstrated that ATBA compound 3-(adamantan-1-yl)-4-methoxy-N-(4-(trifluoromethyl) phenyl) aniline (AMTA) exhibited an inhibitory concentration 50% (IC50) value of 62.84 nM and demonstrated better binding affinity compared to tamoxifen (IC50 = 79.48 nM). Treatment of ERα positive (ER+) mammary carcinoma (MC) cells (Michigan Cancer Foundation-7 (MCF7)) with AMTA significantly decreased cell viability at an IC50 value of 6.4 µM. AMTA treatment of MC cell-generated three-dimensional (3D) spheroids resulted in significantly decreased cell viability. AMTA demonstrated a superior inhibitory effect compared to tamoxifen-treated MC cell spheroids. Subsequently, by use of an oestrogen response element (ERE) luciferase reporter construct, it was demonstrated that AMTA treatment significantly deceased ERE transcriptional activity in MC cells. Concordantly, AMTA treatment of MC cells also significantly decreased protein levels of oestrogen-regulated CCND1 in a dose-dependent manner. In silico molecular docking analysis suggested that AMTA compounds interact with the ligand-binding domain of ERα compared to the co-crystal ligand, 5-(4-hydroxyphenoxy)-6-(3-hydroxyphenyl)-7- methylnaphthalen-2-ol. Therefore, an analogue of AMTA may provide a structural basis to develop a newer class of ERα partial agonists.


Asunto(s)
Antineoplásicos/farmacología , Compuestos de Bifenilo/farmacología , Neoplasias de la Mama , Receptor alfa de Estrógeno , Proteínas de Neoplasias , Animales , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Células MCF-7 , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo
15.
Eur J Med Chem ; 212: 113045, 2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33454462

RESUMEN

In the search for novel, highly potent, and nontoxic adjuvant chemotherapeutics to resolve the major issue of ABC transporter-mediated multidrug resistance (MDR), pyrimidines were discovered as a promising compound class of modern ABCG2 inhibitors. As ABCG2-mediated MDR is a major obstacle in leukemia, pancreatic carcinoma, and breast cancer chemotherapy, adjuvant chemotherapeutics are highly desired for future clinical oncology. Very recently, docking studies of one of the most potent reversers of ABCG2-mediated MDR were reported and revealed a putative second binding pocket of ABCG2. Based on this (sub)pocket, a series of 16 differently 6-substituted 4-anilino-2-phenylpyrimidines was designed and synthesized to explore the potential increase in inhibitory activity of these ABCG2 inhibitors. The compounds were assessed for their influence on the ABCG2-mediated pheophorbide A transport, as well as the ABCB1- and ABCC1-mediated transport of calcein AM. They were additionally evaluated in MDR reversal assays to determine their half-maximal reversal concentration (EC50). The 6-substitution did not only show increased toxicity against ABCG2-overexpressing cells in combination with SN-38 but also a negative influence on cell viability in general. Nevertheless, several candidates had EC50 values in the low double-digit nanomolar concentration range, qualifying them as some of the most potent reversers of ABCG2-mediated MDR. In addition, five novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors were discovered, four of them exerting their inhibitory power against the three stated transporters at least in the single-digit micromolar concentration range.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Diseño de Fármacos , Proteínas de Neoplasias/antagonistas & inhibidores , Pirimidinas/farmacología , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Sitios de Unión/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Perros , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Proteínas de Neoplasias/metabolismo , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad
16.
PLoS One ; 16(1): e0241157, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33406123

RESUMEN

We previously reported that IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminus, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo, we undertook mirror-image peptide phage display using a synthetic D-peptide representing the ANXA1 N-terminus as target. We then identified peptide sequences, synthesized them as D-amino acids, and designated the resulting peptide dTIT7, which we showed bound to the ANXA1 N-terminus. Whole body imaging of mouse brain tumor models injected with near infrared fluorescent IRDye-conjugated dTIT7 showed fluorescent signals in brain and kidney. Furthermore, orally-administered dTIT7/geldanamycin (GA) conjugates suppressed brain tumor growth. Ours is a proof-of-concept experiment showing that ANXA1-binding D-peptide can be developed as an orally-administrable tumor vasculature-targeted therapeutic.


Asunto(s)
Anexina A1/antagonistas & inhibidores , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Proteínas de Neoplasias/antagonistas & inhibidores , Neovascularización Patológica/tratamiento farmacológico , Péptidos , Administración Oral , Animales , Anexina A1/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Int J Mol Sci ; 22(2)2021 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-33435251

RESUMEN

Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4' of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present N-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC50~1 µM) with moderate selectivity over other kinases.


Asunto(s)
Bencilaminas/farmacología , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Neoplasias Pulmonares/enzimología , Quinasas Relacionadas con NIMA/antagonistas & inhibidores , Quinazolinas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bencilaminas/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Mutación , Proteínas de Neoplasias/antagonistas & inhibidores , Quinazolinas/uso terapéutico , Relación Estructura-Actividad
18.
Molecules ; 26(2)2021 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-33419027

RESUMEN

Discovery of the B7 family immune checkpoints such as CTLA-4 (CD152), PD-1 (CD279), as well as their ligands B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), and B7-DC (PD-L2, CD273), has opened new possibilities for cancer immunotherapy using monoclonal antibodies (mAb). The blockade of inhibitory receptors (CTLA-4 and PD-1) with specific mAb results in the activation of cancer patients' T lymphocytes and tumor rejection. However, the use of mAb in clinics has several limitations including side effects and cost of treatment. The development of new low-molecular compounds that block immune checkpoints' functional activity can help to overcome some of these limitations. In this paper, we describe a synthetic peptide (p344) containing 14 amino acids that specifically interact with CTLA-4 protein. A 3D computer model suggests that this peptide binds to the 99MYPPPY104 loop of CTLA-4 protein and potentially blocks the contact of CTLA-4 receptor with B7-1 ligand. Experimental data confirm the peptide-specific interaction with CTLA-4 and its ability to partially block CTLA-4/B7-1 binding. The identified synthetic peptide can be used for the development of novel immune checkpoint inhibitors that can block CTLA-4 functional activity for cancer immunotherapy.


Asunto(s)
Antígeno CTLA-4 , Proteínas de Neoplasias , Neoplasias/tratamiento farmacológico , Péptidos , Antígeno B7-1/antagonistas & inhibidores , Antígeno B7-1/química , Antígeno B7-1/metabolismo , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/química , Antígeno CTLA-4/metabolismo , Humanos , /farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/química , Proteínas de Neoplasias/metabolismo , Neoplasias/química , Neoplasias/metabolismo , Péptidos/química , Péptidos/farmacología
19.
Molecules ; 26(2)2021 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-33429981

RESUMEN

Resident cancer cells with stem cell-like features induce drug tolerance, facilitating survival of glioblastoma (GBM). We previously showed that strategies targeting tumor bioenergetics present a novel emerging avenue for treatment of GBM. The objective of this study was to enhance the therapeutic effects of dual inhibition of tumor bioenergetics by combination of gossypol, an aldehyde dehydrogenase inhibitor, and phenformin, a biguanide compound that depletes oxidative phosphorylation, with the chemotherapeutic drug, temozolomide (TMZ), to block proliferation, stemness, and invasiveness of GBM tumorspheres (TSs). Combination therapy with gossypol, phenformin, and TMZ induced a significant reduction in ATP levels, cell viability, stemness, and invasiveness compared to TMZ monotherapy and dual therapy with gossypol and phenformin. Analysis of differentially expressed genes revealed up-regulation of genes involved in programmed cell death, autophagy, and protein metabolism and down-regulation of those associated with cell metabolism, cycle, and adhesion. Combination of TMZ with dual inhibitors of tumor bioenergetics may, therefore, present an effective strategy against GBM by enhancing therapeutic effects through multiple mechanisms of action.


Asunto(s)
Aldehído Deshidrogenasa/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Glioblastoma , Proteínas de Neoplasias/antagonistas & inhibidores , Esferoides Celulares/enzimología , Aldehído Deshidrogenasa/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/enzimología , Complejo I de Transporte de Electrón/metabolismo , Inhibidores Enzimáticos/farmacología , Glioblastoma/tratamiento farmacológico , Glioblastoma/enzimología , Humanos , Proteínas de Neoplasias/metabolismo , Temozolomida/farmacología
20.
Nat Commun ; 12(1): 647, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510144

RESUMEN

Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and ferroptosis susceptibility.


Asunto(s)
Proteínas de Unión al ADN/genética , Ferroptosis/genética , Regulación Neoplásica de la Expresión Génica , Hierro/metabolismo , Lipocalina 2/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Animales , Línea Celular Tumoral , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/metabolismo , Humanos , Estimación de Kaplan-Meier , Lipocalina 2/metabolismo , Ratones Noqueados , Ratones Desnudos , Ratones Transgénicos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Piperazinas/farmacología , Tratamiento con ARN de Interferencia/métodos , Transducción de Señal/genética , Tiazinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
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