RESUMEN
Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF6, to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs.
Asunto(s)
Apoptosis , Muerte Celular Autofágica , Neoplasias Hepáticas , Células Madre Neoplásicas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Transducción de Señal/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Células Hep G2 , Muerte Celular Autofágica/efectos de los fármacos , Tiazolidinas/farmacología , Animales , Ratones , Movimiento Celular/efectos de los fármacos , Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/químicaRESUMEN
ABSTRACT Background: Spontaneous regression (SR) is defined as the partial or complete disappearance of a tumor, in the absence of a specific treatment. Evidence of the SR in hepatocellular carcinoma (HCC) is rare. Objective: The authors aimed to review all the cases of SR of HCC in two reference centers of Southern Brazil, highlighting the main characteristics. Methods: Data of all patients with HCC were retrospectively reviewed looking for the occurrence of SR in patients from two tertiary centers in Southern Brazil, in the last five years. The diagnosis of cirrhosis was established according to clinical, laboratory and imaging data, as well as upper endoscopy or histopathological examination when necessary. The diagnosis of HCC was based on typical findings according to radiologic criteria (LIRADS) or histopathological examination. Spontaneous regression was defined as a partial or complete involution of a HCC in the absence of a specific therapy. Results: From all cases of HCC in the last 5 years (n=433), there were five cases of SR. Three (60%) were men, the mean age was 62.6 (50.0-76.0) years, and the etiology was HCV in 3 (60%). Complete regression was observed in three patients (60%), one patient (20%) presented partial regression, and one (20%) relapesed and died. The time of follow-up varied between 12 and 21 months. In this presentation, it was highlighted one case of SR observed after COVID-19 infection in a patient with cirrhosis. The possible mechanisms involved in this situation were reviewed, emphasizing the most common like hypoxia and immunological. There were also one patient submitted to a surgical procedure as a possible fator involved and three patients without obvious risk factors. Conclusion: This phenomenon will possibly contribute to a better understanding of the pathophysiological mechanisms of HCC.
RESUMO Contexto: A evidência da regressão espontânea (RE) no carcinoma hepatocelular (CHC) é rara. Objetivo: Revisar todos os casos de RE de CHC em dois centros de referência do Sul do Brasil, destacando as principais características. Métodos: Os dados de todos os pacientes com CHC foram revisados retrospectivamente buscando a ocorrência de RE em pacientes de dois centros terciários do Sul do Brasil, nos últimos 5 anos. O diagnóstico de cirrose foi estabelecido de acordo com dados clínicos, laboratoriais e de imagem, além de endoscopia digestiva alta ou exame histopatológico quando necessário. O diagnóstico de CHC foi baseado em achados típicos de acordo com critérios radiológicos (LIRADS) ou exame histopatológico. A RE foi definida como uma involução parcial ou completa de um CHC na ausência de terapia específica. Resultados: Do total de casos de CHC nos últimos 5 anos (n=433), houve cinco casos de RE. Três (60%) eram homens, a média de idade foi de 62,6 (50,0-76,0) anos, a etiologia foi virus da hepatite C em 3 (60%). A regressão completa foi observada em três pacientes (60%), um paciente (20%) apresentou regressão parcial e um (20%) apresentou recidiva e evoluiu a óbito. O tempo de seguimento variou entre 12 e 21 meses. Nesta apresentação foi destacado um caso (20%) de RE observado após infecção por COVID-19 em paciente com cirrose. Foram revisados os possíveis mecanismos envolvidos nesta situação, enfatizando os mais comuns como hipóxia e imunológicos. Houve também um paciente submetido a procedimento cirúrgico como possível fator envolvido e três pacientes sem fatores de risco evidentes. Conclusão: Este fenômeno possivelmente contribuirá para uma melhor compreensão dos mecanismos fisiopatológicos do CHC.
RESUMEN
Hepatocellular carcinoma (HCC) is considered as the second cause of cancer-related deaths worldwide. Genetic variations are associated with HCC risk, an issue that has been the subject of several meta-analyses. However, meta-analyses have an important limitation on the likelihood of false positive data. Henceforth, this study aimed to assess the level of noteworthiness in the meta-analyses by means of a Bayesian approach. A systematic search was performed for meta-analyses with associations between gene polymorphisms and HCC. The calculations for the False-Positive Rate Probability (FPRP) and the Bayesian False Discovery Probability (BFDP) were performed to assess the noteworthiness with a statistical power of 1.2 and 1.5 of Odds Ratio at a prior probability of 10-3 and 10-5. The quality of studies was evaluated by the Venice criteria. As additional analyses, the gene-gene and protein-protein networks were designed for these genes and products. As results, we found 33 meta-analytic studies on 45 polymorphisms occurring in 35 genes. A total of 1,280 values for FPRP and BFDP were obtained. Seventy-five for FPRP (5.86%) and 95 for BFDP (14.79%) were noteworthy. In conclusion, the polymorphisms in CCND1, CTLA4, EGF, IL6, IL12A, KIF1B, MDM2, MICA, miR-499, MTHFR, PNPLA3, STAT4, TM6SF2, and XPD genes were considered as noteworthy biomarkers for HCC risk.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Teorema de Bayes , Neoplasias Hepáticas/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la EnfermedadRESUMEN
RESUMEN Introducción. El hígado es el mayor órgano sólido, desempeña muchas funciones en el cuerpo. El ejercicio físico es valorado como una intervención no farmacológica eficiente en el fomento del bienestar físico, mental y funcional de pacientes con cáncer. Objetivos. Determinar los efectos del ejercicio físico en el cáncer hepático y sintetizar estudios prospectivos sobre la asociación de la actividad física y el ejercicio físico con el riesgo de cáncer de hígado. Metodología. Revisión sistemática con análisis retrospectivo y descriptivo de artículos científicos publicados en bases de datos indexadas de enero del año 2008 a junio del 2019. Así mismo, se llevó a cabo la selección y evaluación de los archivos por medio de la Declaración de PRISMA, PICO, Cochrane y escala de PEDro. Resultados. Se encontró que la actividad física se asocia con un riesgo reducido de desarrollar cánceres de hígado (IC95%: 0,38-0,80). El ejercicio aeróbico redujo los lípidos hepáticos (grasa hepática 8.9±3.2 a 5.6±1.8%; p <0.05, grasa visceral 54,7±6,0 a 49,6±5,5cm2; p <0,05) y el ejercicio de resistencia aumentó la sensibilidad a la insulina (5.9±5.9 a 4.6±4.6 vs 4.7±2.1 a 5.1±2.5; p<0.05), mejoró la flexibilidad metabólica (-0.0206±0.010 vs 0.004±0.003; p<0.05). Conclusiones. La actividad física y el ejercicio representan un papel importante dentro de la enfermedad del cáncer, ya que se asocia con un menor riesgo de desarrollarlo, así como aminorar la sintomatología que conlleva en especial el cáncer hepático.
ABSTRACT Introduction. The liver is the largest solid organ; it performs many functions in the body. Physical exercise is valued as an efficient non-pharmacological intervention in the promotion of physical, mental and functional well-being of cancer patients. Objectives: To determine the effects of physical exercise on liver cancer and synthesize prospective studies on the association of physical activity and physical exercise with the risk of liver cancer. Methodology. Systematic review with retrospective and descriptive analysis of scientific articles published in indexed databases from January 2008 to June 2019. Likewise, the selection and evaluation of the archives was carried out through the Declaration of PRISMA, PICO, Cochrane and PEDro´s scale. Results. It was found that physical activity is associated with a reduced risk of developing liver cancers (95%CI 0.38-0.80). Aerobic exercise reduced liver lipids (liver fat 8.9±3.2 to 5.6±1.8%; p<0.05, visceral fat 54.7±6.0 to 49.6±5.5cm2; p<0.05) and resistance exercise increased insulin sensitivity (5.9 ± 5.9 to 4.6±4.6 vs. 4.7±2.1 to 5.1±2.5; p <0.05), improved metabolic flexibility (-0.0206± 0.010 vs. 0.004±0.003; p <0.05). Conclusions. Physical activity and exercise represents an important role in cancer disease, since it is associated with a lower risk of developing it, as well as reduce the symptoms which is especially associated with liver cancer.
Asunto(s)
Humanos , Masculino , Femenino , Neoplasias Hepáticas , Neoplasias , Ejercicio Físico , Enfermedad del Hígado Graso no AlcohólicoRESUMEN
Cota tinctoria is a medicinal plant which has been used for management of cancer in folk medicine of various regions. The aim of present study is to investigate cytotoxic activity of different concentrations of hydroalcoholic extract of C. tinctoria flowers on gastric (AGS) and liver (Hep-G2) cancer cell lines as well as Human Natural GUM fibroblast (HUGU) cells. Cell mortality rates were examined after 24, 48 and 72 h incubations using the MTT assay. IC50of extract on AGS cells after 24, 48 and 72h was 1.46, 1.29 and 1.14 µg/mL respectively. The extract demonstrated IC50 of 5.15, 3.92 and 2.89 µg/mL on Hep-G2 cells after 24, 48 and 72 h respectively. No cytotoxic effect was detected on HUGU (Human Natural GUM fibroblast) cells. C. tinctoria seems to have a promising potential to be considered as a source for anticancer drug discovery. However, more experimental and clinical studies are required.
Cota tinctoria es una planta medicinal que se ha utilizado para el tratamiento del cáncer en la medicina popular de varias regiones. El objetivo del presente estudio es investigar la actividad citotóxica de diferentes concentraciones de extracto hidroalcohólico de flores de C. tinctoria en líneas celulares de cáncer gástrico (AGS) e hígado (Hep-G2), así como en células de fibroblasto GUM humano natural (HUGU). Se examinaron las tasas de mortalidad celular después de incubaciones de 24, 48 y 72 h utilizando el ensayo MTT. La CI50 del extracto en células AGS después de 24, 48 y 72 h fue de 1,46; 1,29 y 1,14 µg respectivamente. El extracto demostró una CI50 de 5,15, 3,92 y 2,89 µg/mL en células Hep-G2 después de 24, 48 y 72 h, respectivamente. No se detectó ningún efecto citotóxico en las células HUGU (fibroblasto GUM humano natural). C. tinctoria parece tener un potencial prometedor para ser considerada como una fuente de descubrimiento de fármacos contra el cáncer. Sin embargo, se requieren más estudios experimentales y clínicos.
Asunto(s)
Extractos Vegetales/administración & dosificación , Asteraceae/química , Línea Celular Tumoral/efectos de los fármacos , Neoplasias Hepáticas/tratamiento farmacológico , Antineoplásicos Fitogénicos/administración & dosificación , Neoplasias Gástricas/tratamiento farmacológico , Flavonoides/análisis , Extractos Vegetales/farmacología , Extractos Vegetales/química , Técnicas de Cultivo de Célula , Anthemis/química , Compuestos Fenólicos/análisis , Células Hep G2/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/químicaRESUMEN
PURPOSE: To investigate the prevalence, related risk factors, and survival of intrahepatic cholangiocarcinoma in a Mexican population. MATERIAL AND METHODS: We conducted a cross-sectional study at Medica Sur Hospital in Mexico City with approval of the local research ethics committee. We found cases by reviewing all clinical records of in-patients between October 2005 and January 2016 who had been diagnosed with malignant liver tumors. Clinical characteristics and comorbidities were obtained to evaluate the probable risk factors and the Charlson index. The cases were staged based on the TNM staging system for bile duct tumors used by the American Joint Committee on Cancer and median patient survival rates were calculated using the Kaplan-Meier method. RESULTS: We reviewed 233 cases of hepatic cancer. Amongst these, hepatocellular carcinomas represented 19.3% (n = 45), followed by intrahepatic cholangiocarcinomas, which accounted for 7.7% (n = 18). The median age of patients with intrahepatic cholangiocarcinoma was 63 years, and most of them presented with cholestasis and intrahepatic biliary ductal dilation. Unfortunately, 89% (n = 16) of them were in an advanced stage and 80% had multicentric tumors. Median survival was 286 days among patients with advanced stage tumors (25th-75th interquartile range, 174-645 days). No correlation was found between the presence of comorbidities defined by the Charlson index, and survival. We evaluated the presence of definite and probable risk factors for the development of intrahepatic cholangiocarcinoma, that is, smoking, alcohol consumption, and primary sclerosing cholangitis. DISCUSSION: We found an overall prevalence of intrahepatic cholangiocarcinoma of 7.7%; unfortunately, these patients were diagnosed at advanced stages. Smoking and primary sclerosing cholangitis were the positive risk factors for its development in this population.
Asunto(s)
Neoplasias de los Conductos Biliares/epidemiología , Colangiocarcinoma/epidemiología , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/epidemiología , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/terapia , Colangiocarcinoma/mortalidad , Colangiocarcinoma/patología , Colangiocarcinoma/terapia , Colangitis Esclerosante/epidemiología , Comorbilidad , Estudios Transversales , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , México/epidemiología , Persona de Mediana Edad , Estadificación de Neoplasias , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Fumar/efectos adversos , Fumar/epidemiología , Factores de Tiempo , Resultado del TratamientoRESUMEN
La infección por el Virus de Hepatitis B (VHB) representa un problema de salud pública a escala mundial, estimándose que más de dos millardos de personas en el mundo se han infectado, de los cuales aproximadamente 350 millones son portadores crónicos del virus. Cerca de un millón de muertes al año están relacionadas con hepatocarcinoma primario asociado a la infección por VHB, lo que hace a éste virus la cuarta causa de muerte por enfermedades infecciosas a nivel mundial. La replicación del VHB posee un potencial de variabilidad genética mayor que la de los virus ADN en general favoreciendo la aparición de mutantes naturales generadas por sustituciones puntuales, por reordenamiento de genes, o por cambios en los marcos de lectura denominados genotipos. La variabilidad genética podría estar asociada con las diferentes vías de transmisión, resistencia al interferón o progresión hacia el desarrollo de carcinoma hepatocelular.
Hepatitis B virus (HBV) infection is a worldwide public health problem and it has been estimated that over 2000 million persons have been infected in the world, of approximately 350 million of which are chronic carriers of the virus. Around one million deaths per year are related to primary hepatic cancer associated to HBV infection, which makes this virus the fourth cause of death at a worldwide level. HBV replication has a greater potential of genetic variability than that of DNA viruses in general, favoring the occurrence of natural mutants generated by punctual substitutions, gene reordering, or to changes in the genotype denominated reading frames. Genetic variability could be associated with the various transmission forms, interferon resistance or progression towards the development of hepatocellular cancer.