RESUMEN
Non-small cell lung cancer (NSCLC) has a high mortality rate worldwide. Various treatments strategies have been used against NSCLC including individualized chemotherapies, but innate or acquired cancer cell drug resistance remains a major obstacle. Recent studies revealed that the Kelch-like ECH associated protein 1/Nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) pathway is intimately involved in cancer progression and chemoresistance. Thus, antagonizing Nrf2 would seem to be a viable strategy in cancer therapy. In the present study a traditional Chinese medicine, triptolide, was identified that markedly inhibited expression and transcriptional activity of Nrf2 in various cancer cells, including NSCLC and liver cancer cells. Consequently, triptolide made cancer cells more chemosensitivity toward antitumor drugs both in vitro and in a xenograft tumor model system using lung carcinoma cells. These results suggest that triptolide blocks chemoresistance in cancer cells by targeting the Nrf2 pathway. Triptolide should be further investigated in clinical cancer trials.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Elementos de Respuesta Antioxidante/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Diterpenos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Factor 2 Relacionado con NF-E2/antagonistas & inhibidores , Fenantrenos/administración & dosificación , Células A549 , Animales , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Elementos de Respuesta Antioxidante/fisiología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/fisiología , Compuestos Epoxi/administración & dosificación , Células Hep G2 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Carga Tumoral/fisiología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout (KO) of selenocysteine-tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). These Trsp-KO (TrspRIPKO) mice exhibit deletion of Trsp in both hypothalamic cells and pancreatic ß cells, leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals are suppressed, and numbers of proopiomelanocortin-positive neurons in the hypothalamus are decreased. In contrast, Trsp-KO mice (TrspIns1KO) expressing Cre specifically in pancreatic ß cells, but not in the hypothalamus, do not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related factor 2) regulates antioxidant gene expression. Increased Nrf2 signaling suppresses hypothalamic oxidative stress and improves insulin and leptin resistance in TrspRIPKO mice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.
Asunto(s)
Hipotálamo/metabolismo , Resistencia a la Insulina/fisiología , Leptina/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/fisiología , Animales , Antioxidantes/metabolismo , Diabetes Mellitus/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Ratones , Ratones Noqueados , Regiones Promotoras Genéticas/fisiología , ARN de Transferencia Aminoácido-Específico/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Oleanolic acid (OA) is a natural triperpenoid that protects against a variety of hepatotoxicants such as carbon tetrachloride, cadmium, acetaminophen, and bromobenzene. To gain insight into the molecular mechanisms of this generalized hepatoprotection, genomic analysis was performed on mouse and rat livers after OA treatment. Mice and rats were given OA at a hepatoprotective dose (50 micromol/kg, s.c., daily for 4 days) and hepatic RNA was isolated, purified, and subjected to gene expression analysis. OA treatment produced changes in 5% of the genes on custom-designed mouse liver array and rat toxicology-II array. Changes in key gene expressions were further analyzed by real-time RT-PCR. OA treatment dramatically increased expression of hepatic metallothionein (Mt), and increased the expression of the nuclear factor E2-related factor 2 (Nrf2), NAD(P)H:quinone oxidoreductase 1 (Nqo1), heme oxygenase-1 (Hmox1), and glutamate-cysteine ligases (Gclc and Gclm). OA treatment also increased the expression of genes related to cell proliferation and suppressed the expression of several cytochrome P450 genes possibly to switch cellular metabolic energy to an acute-phase response. Hepatic MT protein was increased 60- and 15-fold in mice and rats, respectively, together with a 30% increase in mouse liver zinc. These gene expression changes, particularly the dramatic induction of MT and the Nrf2 signaling, occur with hepatoprotection doses of OA, and likely are important in the generalized protective effects of OA against hepatotoxicants.
Asunto(s)
Hígado/efectos de los fármacos , Metalotioneína/genética , Factor 2 Relacionado con NF-E2/genética , Ácido Oleanólico/farmacología , Sustancias Protectoras/farmacología , Animales , ADN Complementario/genética , Perfilación de la Expresión Génica , Hígado/metabolismo , Masculino , Metalotioneína/metabolismo , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Sprague-Dawley , Zinc/metabolismoRESUMEN
Epigallocatechin-3-gallate (EGCG), a main catechin of green tea, has been suggested to inhibit hepatic gluconeogenesis. However, the exact role and related mechanism have not been established. In this study, we examined the role of EGCG in hepatic gluconeogenesis at concentrations that are reachable by ingestion of pure EGCG or green tea, and are not toxic to hepatocytes. Our results show in isolated hepatocytes that EGCG at relatively low concentrations (Asunto(s)
Catequina/análogos & derivados
, Gluconeogénesis/efectos de los fármacos
, Hígado/efectos de los fármacos
, Complejos Multienzimáticos/fisiología
, Proteínas Serina-Treonina Quinasas/fisiología
, Proteínas Quinasas Activadas por AMP
, Animales
, Antioxidantes/farmacología
, Catequina/farmacología
, Hepatocitos/metabolismo
, Peróxido de Hidrógeno/química
, Insulina/metabolismo
, Hígado/metabolismo
, Ratones
, Modelos Biológicos
, Complejos Multienzimáticos/metabolismo
, Proteínas Serina-Treonina Quinasas/metabolismo
, ARN Interferente Pequeño/metabolismo
, Especies Reactivas de Oxígeno
, Transducción de Señal
, Té