RESUMEN
BACKGROUND: Cisplatin and carboplatin cause nephrotoxicity by forming platinum-DNA adducts and lead to cell death. METHODS: One-hundred and sixteen Taiwanese lung cancer patients who received cisplatin or carboplatin more than twice were recruited, and their genotypes were determined. The risk of renal dysfunction, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage kidney disease (RIFLE) criteria were used to evaluate the occurrence of nephrotoxicity. A logistic regression, multiple regression with a classification and regression tree (CART), and the Framingham study risk score were used to analyze interactions between genetic and nongenetic factors in producing platinum-induced nephrotoxicity. RESULTS: ERCC1 118C and TP53 72Arg polymorphisms were associated with increased risks of platinum-induced nephrotoxicity. Other risk factors found included the platinum type, baseline serum creatinine (Scr), coadministration of vinorelbine, and the number of chemotherapy cycles. The overall prediction rate of the CART was 82.7%, with a sensitivity of 0.630 and specificity of 0.896. The Framingham study risk prediction model contained 7 factors. Its prediction rate was 84.5%, with a sensitivity of 0.643 and specificity of 0.909. CONCLUSIONS: Genetic polymorphisms of ERCC1 and TP53 are risk factors for nephrotoxicity. The CART analysis may provide a clinically applicable model to predict the risk of cisplatin- and carboplatin-induced nephrotoxicity.
Asunto(s)
Carboplatino/uso terapéutico , Cisplatino/uso terapéutico , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Enfermedades Renales/epidemiología , Enfermedades Renales/genética , Enfermedades Pulmonares/tratamiento farmacológico , Proteína p53 Supresora de Tumor/genética , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Niño , Comorbilidad , Creatinina/sangre , Interpretación Estadística de Datos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/sangre , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Humanos , Incidencia , Enfermedades Renales/sangre , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Modelos de Riesgos Proporcionales , Medición de Riesgo/métodos , Distribución por Sexo , Taiwán/epidemiología , Adulto JovenRESUMEN
The induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of various cancer cells. Osthole, a natural coumarin derivative extracted from traditional Chinese medicines, is known to inhibit the proliferation of a variety of tumor cells, but the effect of osthole on the invasiveness of tumor cells is largely unknown. This study determines whether and by what mechanism osthole inhibits invasion in CL1-5 human lung adenocarcinoma cells. Herein, we found that osthole effectively inhibited the migratory and invasive abilities of CL1-5 cells. A zymographic assay showed that osthole inhibited the proteolytic activity of MMP-9 in CL1-5 cells. Inhibition of migration, invasion, and MMP2 and/or MMP-9 proteolytic activities was also observed in other lung adenocarcinoma cell lines (H1299 and A549). We further found that osthole inhibited MMP-9 expression at the messenger RNA and protein levels. Moreover, a chromatin immunoprecipitation assay showed that osthole inhibited the transcriptional activity of MMP-9 by suppressing the DNA binding activity of nuclear factor (NF)-κB in the MMP-9 promoter. Using reporter assays with point-mutated promoter constructs further confirmed that the inhibitory effect of osthole requires an NF-κB binding site on the MMP-9 promoter. Western blot and immunofluorescence assays demonstrated that osthole inhibited NF-κB activity by inhibiting IκB-α degradation and NF-κB p65 nuclear translocation. In conclusion, we demonstrated that osthole inhibits NF-κB-mediated MMP-9 expression, resulting in suppression of lung cancer cell invasion and migration, and osthole might be a potential agent for preventing the invasion and metastasis of lung cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Cumarinas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Metaloproteinasa 9 de la Matriz/genética , Adenocarcinoma/patología , Sitios de Unión , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Técnica del Anticuerpo Fluorescente , Humanos , Neoplasias Pulmonares/patología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Medicina Tradicional China , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Invasividad Neoplásica , Regiones Promotoras Genéticas , ARN Mensajero/metabolismoRESUMEN
Oral cancer mortality has increased during the last decade due to the difficulties in treating related metastasis. Dioscorea nipponica Makino, a popular folk medicine, exerts anti-obesity and anti-inflammation properties. However, the effect of this folk medicine on metastasis of oral cancer has yet to be fully elucidated. The present study demonstrates that D. nipponica extracts (DNE), at a range of concentrations (0-50 µg/mL), concentration-dependently inhibited migration/invasion capacities of human oral cancer cells, HSC-3, without cytotoxic effects. The anti-migration effect of DNE was also observed in two other OSCC cell lines, Ca9-22 and Cal-27. Zymography, real time PCR, and Western blotting analyses revealed that DNE inhibited matrix metalloproteinase-2 (MMP-2) enzyme activity, and RNA and protein expression. The inhibitory effects of DNE on MMP-2 proceeded by up-regulating tissue inhibitor of metalloproteinase-2 (TIMP-2), as well as suppressing nuclear translocation and DNA binding activity of cAMP response element-binding (CREB) and activating protein-1 (AP-1) on the MMP-2 promoter in HSC-3 cells. In conclusion, DNE inhibited the invasion of oral cancer cells and may have potential use as a chemopreventive agent against oral cancer metastasis.
Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dioscorea/química , Inhibidores de la Metaloproteinasa de la Matriz , Neoplasias de la Boca/patología , Extractos Vegetales/farmacología , Factor de Transcripción AP-1/metabolismo , Transcripción Genética , Secuencia de Bases , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Cartilla de ADN , Citometría de Flujo , Humanos , Metaloproteinasa 2 de la Matriz/genética , Neoplasias de la Boca/enzimología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Identifying the risk factors responsible for lung cancer especially for nonsmokers is critical for both its prevention and treatment. Studies have linked the polymorphisms in N-acetyltransferases (NAT2), a key enzyme for metabolism of hydrocarbons, with lung cancer in Asian female nonsmokers. Since a high percentage of lung adenocarcinoma in Asian female nonsmokers contains activating hotspot mutations in epidermal growth factor receptors (EGFR), we hypothesized that NAT2 polymorphisms might represent a risk factor in lung cancer with EGFR mutations. We studied NAT polymorphisms in 117 nonsmall cell lung cancer (NSCLC) patients and in 119 healthy controls and EGFR hotspot mutations in exons 18-21 in 100 of the 117 patients using polymerase chain reactions. NAT2 fast acetylator genotypes were significantly associated with patients with lung cancer (P = 0.04, odds ratio (OR): 1.90, 95% confidence interval (CI): 1.02-3.57). Further analyses revealed that NAT2 fast acetylator genotypes were significantly associated with NSCLC with wildtype EGFR (P = 0.008, OR: 3.16, 95% CI: 1.31-7.63), but not with those with EGFR mutations (P = 0.40). Therefore, NAT2 fast acetylator genotypes are a potential risk factor especially for lung cancer with wildtype EGFR.