RESUMO
This study reports the antimigration, anti-invasive effect of glabridin, a flavonoid obtained from licorice, in human non-small cell lung cancer A549 cells. Glabridin exhibited effective inhibition of cell metastasis by decreasing cancer cell migration and invasion of A549 cells. In addition, glabridin also decreased A549-mediated angiogenesis. Further investigation revealed that glabridin's inhibition of cancer angiogenesis was also evident in a nude mice model. Blockade of A549 cells migration was associated with an increase of ανß3 integrin proteosome degradation. Glabridin also decreased the active forms of FAK and Src, and enhanced levels of inactivated phosphorylated Src (Tyr 527), decreasing the interaction of FAK and Src. Inhibition of the FAK/Src complex by glabridin also blocked Akt activation, resulting in reduced activation of RhoA and myosin light chain phosphorylation. This study demonstrates that glabridin may be a novel anticancer agent for the treatment of lung cancer in 3 different ways: inhibition of migration, invasion, and angiogenesis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/efeitos dos fármacos , Isoflavonas/farmacologia , Neoplasias Pulmonares/metabolismo , Fenóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/efeitos dos fármacos , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Integrina beta3/efeitos dos fármacos , Integrina beta3/metabolismo , Neoplasias Pulmonares/enzimologia , Camundongos , Camundongos Nus , Cadeias Leves de Miosina/metabolismo , Neovascularização Patológica/enzimologia , Neovascularização Patológica/metabolismo , Fosforilação/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/metabolismo , Quinases da Família src/efeitos dos fármacos , Quinases da Família src/metabolismoRESUMO
This study investigates the anticancer effect of dehydrocostuslactone (DHE), a medicinal plant-derived sesquiterpene lactone, on human non-small cell lung cancer cell lines, A549, NCI-H460 and NCI-H520. Our results show that DHE inhibits the proliferation of A549, NCI-H460 and NCI-H520 cells. DHE-induced apoptosis in both A549 and NCI-H460 cells. DHE triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels, PKR-like ER kinase (PERK) phosphorylation, inositol requiring protein 1 (IRE1) and CHOP/GADD153 upregulation, X-box transcription factor-1 (XBP-1) mRNA splicing, and caspase-4 activation. The release of calcium triggered the production of ROS, which further enhances calcium overloading and subsequently activates p38, JNK and ERK1/2. Both IRE1 miRNA transfection and BAPTA-AM pretreatment inhibit DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death through ER stress. Importantly, a novel anticancer agent for the treatment of non-small cell lung cancer, and is supported by animal studies which have shown a dramatic 50% reduction in tumor size after 28 days of treatment. This study demonstrates that DHE may be a novel anticancer agent for the treatment of non-small cell lung cancer.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Retículo Endoplasmático/efeitos dos fármacos , Lactonas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Sesquiterpenos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Caspases Iniciadoras/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Retículo Endoplasmático/metabolismo , Endorribonucleases/genética , Endorribonucleases/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Nus , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Transplante de Neoplasias , Estresse Oxidativo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio , Fatores de Transcrição de Fator Regulador X , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição CHOP/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Carga Tumoral/efeitos dos fármacos , Proteína 1 de Ligação a X-Box , eIF-2 Quinase/metabolismoRESUMO
Aucubin, an iridoid glycoside isolated from the leaves of Aucuba japonica, inhibits human non-small cell lung cancer A549 cells by blocking cell cycle progression in the G(0)/G(1) phase and inducing apoptosis. An ELISA showed that the G(0)/G(1) phase arrest is due to p53-mediated induction of p21. Enhancement of Fas and its two ligands, membrane-bound and soluble Fas ligand, may be responsible for the apoptotic effect induced by aucubin. The present study shows, for the first time, that the induction of p53 and activity of the Fas/Fas ligand apoptotic system may participate in the antiproliferative activity of aucubin in A549 cells.