RESUMEN
PURPOSE: Estrogen plays a critical role in the invasiveness and metastasis of non-small cell lung cancer (NSCLC) through estrogen receptor ß (ERß). However, the antimetastatic effect of the ERß antagonist fulvestrant was still limited in NSCLC patients. Recently, Toll-like receptor 4 (TLR4) signaling was implicated in NSCLC metastasis. Our present study aimed to evaluate the synergistic antimetastatic effect of a combination of fulvestrant and the TLR4-specific inhibitor CLI-095 (TAK-242) on human NSCLC cells. METHODS: The expression levels of ERß and TLR4 were detected by immunohistochemical (IHC) analysis of 180 primary NSCLC and 30 corresponding metastatic lymph node samples. The association between ERß and TLR4 expression was analyzed. The aggressiveness of NSCLC cells treated with fulvestrant, CLI-095 or the drug combination and formation status of their invadopodia, invasion-associated structures, were investigated. The protein levels in NSCLC cells in different groups were determined by Western blot and immunofluorescence analyses. RESULTS: Here, a positive correlation between ERß and TLR4 expression was observed in both primary NSCLC tissue (Spearman's Rho correlation coefficient = 0.411, p < 0.001) and metastatic lymph node tissue (Spearman's Rho correlation coefficient = 0.374, p = 0.009). The protein levels of ERß in NSCLC cell lines were decreased by fulvestrant, and this suppressive effect was significantly enhanced when fulvestrant was combined with CLI-095 (p < 0.05). Both the migration and invasion of NSCLC cells were suppressed by fulvestrant or CLI-095 alone, and the combination of fulvestrant + CLI-095 showed the strongest inhibitory effect (p < 0.05). In addition, the results demonstrated that CLI-095 also helped fulvestrant restrict the formation and function of invadopodia in NSCLC cells (p < 0.05). CONCLUSIONS: Collectively, our study results suggested that CLI-095 enhances the antimetastatic effect of fulvestrant on NSCLC and provided support for further investigation of the antitumor activity of combined therapy with antiestrogen and anti-TLR4 agents in the clinic.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Antagonistas del Receptor de Estrógeno/uso terapéutico , Fulvestrant/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Metástasis de la Neoplasia/prevención & control , Sulfonamidas/uso terapéutico , Receptor Toll-Like 4/antagonistas & inhibidores , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Movimiento Celular/efectos de los fármacos , Receptor beta de Estrógeno/fisiología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Receptor Toll-Like 4/fisiologíaRESUMEN
The purpose of this study was to explore the radiotherapy sensitization effects and the mechanism of capecitabine (Xeloda) against the non-small-cell lung cancer cell line, A549. γ-[(60)Co] radiation was used as the intervention method. Proliferative inhibition of capecitabine on A549 cells was determined by the CCK-8 method. The effects of capecitabine on the apoptosis rate and cell cycle distribution of A549 were detected with the flow cytometric method. We found that capecitabine inhibited the proliferation of A549 in a dose-dependent manner, notably increased the cell apoptosis rate and blocked the cellular G0/G1 phase after radiotherapy by γ-[(60)Co]. Therefore, capecitabine can significantly increase the radiosensitivity of A549; its mechanism may be related to cell cycle arrest and induction of apoptosis.