RESUMO
A novel compound, acetyltanshinone IIA (ATA) was obtained from chemical modifications of tanshinone TIIA (TIIA) isolated from a medicinal plant, Salvia miltiorrhiza. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed a higher growth inhibition ability on breast cancer especially HER2 positive cells than normal cells and it inhibited xenografted tumor growth in mice. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death. ATA-mediated ROS production and its downstream apoptotic events could be blocked by an antioxidant agent, propyl gallate, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein reduced ATA-induced cell death. In conclusion, ATA is a novel anticancer agent with potent in vitro and in vivo anticancer ability. ROS-mediated Bax activation should be the mechanism by which ATA induces apoptosis and inhibits tumor growth.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Fenantrenos/farmacologia , Carga Tumoral/efeitos dos fármacos , Abietanos , Animais , Antineoplásicos Fitogênicos/síntese química , Antioxidantes/farmacologia , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Citocromos c/metabolismo , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Feminino , Células HL-60 , Células HeLa , Células Hep G2 , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/farmacologia , Fenantrenos/síntese química , Galato de Propila/farmacologia , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor ErbB-2/metabolismo , Solubilidade , Fatores de Tempo , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína X Associada a bcl-2/metabolismoRESUMO
Bioassay-guided fractionation of the acetone extract of the bark of Garcinia oblongifolia has resulted in the isolation of three new xanthones, oblongixanthones A-C (1-3), three new polyprenylated benzoylphloroglucinols, oblongifolins E-G (4-6), and 12 known compounds. Oblongifolins I (5) and J (6) are the first natural products that have similar structural features to those of two known oxidation products of garcinol. The structures of the new compounds 1-6 were characterized by spectroscopic data interpretation. All isolates were assayed for their apoptosis-inducing effects against HeLa-C3 cells. Oblongifolin C (16) was found to be the most potent apoptotic inducer of the compounds evaluated.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Medicamentos de Ervas Chinesas/isolamento & purificação , Garcinia/química , Plantas Medicinais/química , Xantonas/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Células HeLa , Humanos , Estrutura Molecular , Casca de Planta/química , Xantonas/química , Xantonas/farmacologiaRESUMO
Three new prenylated xanthones, 1-3, along with ten known compounds, were isolated from the stem bark of Garcinia lancilimba. Their structures were elucidated by extensive spectroscopic analysis, including 1D- and 2D-NMR spectra, as well as HR-MS experiments. Some of these compounds showed apoptotic effects or growth-inhibition effects against HeLa cells expressing a caspase sensor protein.
Assuntos
Antineoplásicos/química , Apoptose , Clusiaceae/química , Xantonas/química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Caspases/metabolismo , Linhagem Celular , Transferência Ressonante de Energia de Fluorescência , Células HeLa , Humanos , Casca de Planta/química , Caules de Planta/química , Plantas Medicinais , Xantonas/isolamento & purificação , Xantonas/farmacologiaRESUMO
Bioassay and ultraperformance liquid chromatography/photodiode array/mass spectrometry (UPLC/PDA/MS) guided isolation of the apoptosis-inducing active metabolites on HeLa-C3 cells from the pericarp of Garcinia yunnanensis (Guttiferae) yielded five active compounds, including the new garciyunnanins A (1) and B (2). The structures of the compounds were elucidated by comprehensive nuclear magnetic resonance and mass spectrometry analysis. Garciyunnanin B (2), featured with a natural tetracyclic xanthone skeleton derived from a polyisoprenylated benzophenone, is structurally interesting since it can be seen as an evidence of the previously described cyclization of garcinol by 2,2-diphenyl-1-picrylhydrazyl (DPPH). Garciyunnanin A (1) contains a 3-monohydroxy benzophenone skeleton, which is rarely found in Garcinia species. Both new compounds induce HeLa-C3 cells into apoptosis after 72 h of incubation at 15 microM. It is noteworthy that oblongifolin C (4), the major constituent of this plant, has proved to be the most active one among the isolates for inducing apoptotic cell death in cervical cancer derived HeLa-C3 sensor cells.