RESUMO
Dendrobium nobile is widely used as an analgesic, an antipyretic, and a tonic to nourish the stomach in traditional medicine. Mounting evidence suggests an antitumor activity of denbinobin, a major phenanthrene isolated from stems of Dendrobium nobile. The present study aimed to investigate the inhibitory effect of denbinobin on the invasive ability of human cancer cells. The cytotoxicity of denbonobin was examined in several human cancer cell lines including SK-Hep-1 hepato-carcinoma cells, SNU-484 gastric cancer cells, and HeLa cervix cancer cells. Because SNU-484 cells showed the lowest IC50 value, we examined the effect of denbinobin on the invasive ability of SNU-484 cells. The present study revealed, for the first time, that denbinobin inhibits the invasive phenotype of SNU-484 human gastric cancer cells in a dose-dependent manner. Expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were significantly decreased by denbinobin, suggesting that MMP-2/-9 may be responsible for the anti-invasive activity of denbinobin. We also provide evidence that denbinobin induces apoptosis through down-regulation of Bcl-2 and an up-regulation of Bax. Taken together, this study demonstrates that denbinobin inhibits invasion and induces apoptosis in highly invasive SNU-484 human gastric cancer cells. Given that gastric cancer has been estimated to be one of the most common causes of cancer-related death among Asians and the major cause of death from gastric cancer is the metastatic spread of the disease, our findings may provide useful information regarding the application of denbinobin as a chemopreventive agent that could prevent or alleviate metastatic gastric cancer.
Assuntos
Antraquinonas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Fenantrenos/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Calgranulina A/antagonistas & inibidores , Calgranulina A/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quimioprevenção/métodos , Dendrobium/química , Regulação para Baixo/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/efeitos dos fármacos , Células HeLa , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Inibidores de Metaloproteinases de Matriz , Invasividade Neoplásica , Fenótipo , Preparações de Plantas/farmacologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: The p38 mitogen-activated protein kinase (MAPK) is activated by various pro-inflammatory and stressful stimuli. Mounting evidence suggests that the p38 MAPK signaling cascade is involved in various biological responses other than inflammation such as cell proliferation, differentiation, apoptosis and invasion, suggesting that the p38 MAPK can serve as a potential therapeutic target for the treatment of not only inflammatory diseases but also cancer. METHODS: The unique characteristics of p38 MAPK are summarized with regard to activation and function of p38 MAPK signaling cascades. We then discuss the involvement of p38 MAPK in diseases and the implications of the possible therapeutic use of p38 MAPK inhibitors. The p38 MAPK inhibitors that have been used in the in vitro/in vivo systems as well as in the clinical trials are summarized. RESULTS/CONCLUSION: The p38 MAPK plays an important role in key cellular processes related to inflammation and cancer. Understanding the signal transduction mechanisms and gene regulation by p38 MAPK provides useful information in the development of p38 MAPK inhibitors with therapeutic benefits with reduced side effects. In this review, we summarize and present the list of p38 MAPK inhibitors in in vitro/in vivo studies as well as in clinical trials.