RESUMEN
OBJECTIVE: Bladder cancer is one of the most prevalent genitourinary malignancies. Despite active chemotherapy regimens, patients with bladder cancer suffer from a high rate of tumor recurrence. Thus, new approaches and agents to improve quality of life and survival still need to be developed. The objective of the present study was to evaluate the effect and underlying mechanisms of boldine, an aporphine alkaloid of Peumus boldus, on bladder cancer proliferation and cell death. METHODS: Sulforhodamine B assay, Tetrazolium reduction assay, Flow Cytometry Analysis, Ecto-5'-nucleotidase activity and Western blot assay were performed. RESULTS: The results showed that boldine was able to reduce cell viability and cell proliferation in T24 cells. In addition, boldine arrests the cell cycle at G2/M-phase and cause cell death by apoptosis. Boldine-induced inhibition of cell growth and cell cycle arrest appears to be linked to inactivation of extracellular signal-regulated kinase protein (ERK). Additionally, the efficacy of boldine in apoptosis-induced in T24 cells is correlated with modulation of AKT (inactivation) and glycogen synthase kinase-3ß (GSK-3ß) (activation) proteins. CONCLUSIONS: The present findings may, in part, explain the therapeutic effects of boldine for treatment of urinary bladder cancer.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis , Aporfinas/farmacología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Neoplasias de la Vejiga Urinaria/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular , Ensayos de Selección de Medicamentos Antitumorales , Glucógeno Sintasa Quinasa 3 beta , Humanos , Peumus/química , Extractos Vegetales/farmacología , Rodaminas , Transducción de Señal , Sales de Tetrazolio , Tiazoles , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
PURPOSE This phase III, multicenter, randomized, placebo-controlled trial assessed the efficacy and safety of sorafenib, an oral multikinase inhibitor, in combination with carboplatin and paclitaxel in chemotherapy-naïve patients with unresectable stage IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Nine hundred twenty-six patients were randomly assigned to receive up to six 21-day cycles of carboplatin area under the curve 6 and paclitaxel 200 mg/m(2) (CP) on day 1, followed by either sorafenib 400 mg twice a day (n = 464, arm A) or placebo (n = 462, arm B) on days 2 to 19. The maintenance phase after CP consisted of sorafenib 400 mg or placebo twice a day. The primary end point was overall survival (OS); secondary end points included progression-free survival and tumor response. RESULTS Overall demographics were balanced between arms; 223 patients (24%) had squamous cell histology. On the basis of a planned interim analysis, median OS was 10.7 months in arm A and 10.6 months in arm B (hazard ratio [HR] = 1.15; 95% CI, 0.94 to 1.41; P = .915). The study was terminated after the interim analysis concluded that the study was highly unlikely to meet its primary end point. A prespecified exploratory analysis revealed that patients with squamous cell histology had greater mortality in arm A than in arm B (HR = 1.85; 95% CI, 1.22 to 2.81). Main grade 3 or 4 sorafenib-related toxicities included rash (8.4%), hand-foot skin reaction (7.8%), and diarrhea (3.5%). CONCLUSION No clinical benefit was observed from adding sorafenib to CP chemotherapy as first-line treatment for NSCLC.