RESUMO
Rosmarinic acid (RA), a main phenolic compound contained in rosemary which is used as tea, oil, medicine and so on, has been known to present anti-inflammatory, anti-oxidant and anti-cancer effects. Histone deacetylases (HDACs) are enzymes that play important roles in gene expression by removing the acetyl group from histone. The aberrant expression of HDAC in human tumors is related with the onset of human cancer. Especially, HDAC2, which belongs to HDAC class I composed of HDAC 1, 2, 3 and 8, has been reported to be highly expressed in prostate cancer (PCa) where it downregulates the expression of p53, resulting in an inhibition of apoptosis. The purpose of this study is to investigate the effect of RA in comparison with suberoylanilide hydroxamic acid (SAHA), an HDAC inhibitor used as an anti-cancer agent, on survival and apoptosis of PCa cell lines, PC-3 and DU145, and the expression of HDAC. RA decreased the cell proliferation in cell viability assay, and inhibited the colony formation and tumor spheroid formation. Additionally, RA induced early- and late-stage apoptosis of PC-3 and DU145 cells in Annexin V assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively. In western blot analysis, RA inhibited the expression of HDAC2, as SAHA did. Proliferating cell nuclear antigen (PCNA), cyclin D1 and cyclin E1 were downregulated by RA, whereas p21 was upregulated. In addition, RA modulated the protein expression of intrinsic mitochondrial apoptotic pathway-related genes, such as Bax, Bcl-2, caspase-3 and poly (ADP-ribose) polymerase 1 (PARP-1) (cleaved) via the upregulation of p53 derived from HDAC2 downregulation, leading to the increased apoptosis of PC-3 and DU145 cells. Taken together, treatment of RA to PCa cell lines inhibits the cell survival and induces cell apoptosis, and it can be used as a novel therapeutic agent toward PCa.
Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Cinamatos/análise , Depsídeos/análise , Histona Desacetilase 2/metabolismo , Rosmarinus/química , Anexina A5 , Caspase 3/genética , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Ciclina E/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Regulação da Expressão Gênica , Histona Desacetilase 2/genética , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Neoplasias da Próstata/metabolismo , Transdução de Sinais , Chás de Ervas , Chás Medicinais , Vorinostat/análise , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo , Ácido RosmarínicoRESUMO
Asiatic acid (AA) is one of the major components of Titrated extract of Centella asiatica (TECA), which has been reported to possess antioxidant and anti-inflammatory activities. The purpose of this study was to investigate the protective effect of AA on pulmonary inflammation induced by cigarette smoke (CS). AA significantly attenuated the infiltration of inflammatory cells in bronchoalveolar lavage fluid (BALF) of CS exposure mice. AA also decreased ROS production and NE activity, and inhibited the release of proinflammatory cytokines in BALF. AA reduced the recruitment of inflammatory cells and MCP-1 expression in lung tissue of CS exposure mice. AA also attenuated mucus overproduction, and decreased the activation of MAPKs and NF-kB in lung tissue. Furthermore, AA increased HO-1 expression and inhibited the reduced expression of SOD3 in lung tissue. These findings indicate that AA effectively inhibits pulmonary inflammatory response, which is an important process in the development of chronic obstructive pulmonary disease (COPD) via suppression of inflammatory mediators and induction of HO-1. Therefore, we suggest that AA has the potential to treat inflammatory disease such as COPD.