RESUMO
BACKGROUND AND PURPOSE: The effects of 4-O-methylhonokiol (MH), a constituent of Magnolia officinalis, were investigated on human prostate cancer cells and its mechanism of action elucidated. EXPERIMENTAL APPROACH: The anti-cancer effects of MH were examined in prostate cancer and normal cells. The effects were validated in vivo using a mouse xenograft model. KEY RESULTS: MH increased the expression of PPARγ in prostate PC-3 and LNCap cells. The pull-down assay and molecular docking study indicated that MH directly binds to PPARγ. MH also increased transcriptional activity of PPARγ but decreased NF-κB activity. MH inhibited the growth of human prostate cancer cells, an effect attenuated by the PPARγ antagonist GW9662. MH induced apoptotic cell death and this was related to G(0) -G(1) phase cell cycle arrest. MH increased the expression of the cell cycle regulator p21, and apoptotic proteins, whereas it decreased phosphorylation of Rb and anti-apoptotic proteins. Transfection of PC3 cells with p21 siRNA or a p21 mutant plasmid on the cyclin D1/ cycline-dependent kinase 4 binding site abolished the effects of MH on cell growth, cell viability and related protein expression. In the animal studies, MH inhibited tumour growth, NF-κB activity and expression of anti-apoptotic proteins, whereas it increased the transcriptional activity and expression of PPARγ, and the expression of apoptotic proteins and p21 in tumour tissues. CONCLUSIONS AND IMPLICATION: MH inhibits growth of human prostate cancer cells through activation of PPARγ, suppression of NF-κB and arrest of the cell cycle. Thus, MH might be a useful tool for treatment of prostate cancer.
Assuntos
Antineoplásicos/farmacologia , Compostos de Bifenilo/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Lignanas/farmacologia , NF-kappa B/metabolismo , PPAR gama/agonistas , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Compostos de Bifenilo/uso terapêutico , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Lignanas/uso terapêutico , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The self-assembly of helical peptides and information transfer through autocatalysis and cross-catalysis are the foundation of peptide-based molecular evolution models. Many fundamental properties of living systems, such as environmental sensitivity, chiroselectivity, cross-catalysis, dynamic error correction and conditional selection, are exhibited by various self-replicating peptide systems. Recently, advances have been made in the design of peptide systems with autocatalytic and cross-catalytic properties.
Assuntos
Proteínas de Ligação a DNA , Proteínas Fúngicas/química , Peptídeos/química , Peptídeos/síntese química , Proteínas Quinases/química , Proteínas de Saccharomyces cerevisiae , Sequência de Aminoácidos/genética , Catálise , Evolução Molecular , Modelos Moleculares , Conformação Molecular , Fatores de Iniciação de Peptídeos , Engenharia de ProteínasRESUMO
The synthesis of a new series of 1 beta-methylcarbapenems having a 1,3-diazabicyclo[3.3.0]octane-2,4-dione moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bateria are determined and the effect of substituent on the bicyclic ring as well as stereoisomerism was investigated.
