RESUMO
Nine quillaic acid and five gypsogenin bisdesmosides were isolated from roots of Saponaria officinalis L. (Caryophyllaceae). Seven of the quillaic acid saponins possessed a 3-O-ß-D-galactopyranosyl-(1 â 2)-[ß-D-xylopyranosyl-(1 â 3)]-ß-D-glucuronopyranosyl unit, but differed from each other in oligosaccharide units linked to the C-28 ester. The five gypsogenin saponins isolated from the roots all possessed the 3-O-ß-D-galactopyranosyl-(1 â 2)-[ß-D-xylopyranosyl-(1 â 3)]-ß-D-glucuronopyranosyl unit, with their oligosaccharide units linked to the C-28 ester differing. Structures were elucidated by extensive 1D and 2D NMR spectroscopy and mass spectrometry. The saponins were evaluated for growth inhibitory activity in two human cancer cell lines and hemolytic activity in sheep red blood cells.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Ácido Oleanólico/análogos & derivados , Saponaria/química , Saponinas/isolamento & purificação , Saponinas/farmacologia , Animais , Antineoplásicos Fitogênicos/química , Caryophyllaceae/química , Humanos , Ressonância Magnética Nuclear Biomolecular , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , Raízes de Plantas/química , Saponinas/química , Ovinos , Triterpenos/químicaRESUMO
The unfolded protein response (UPR) is activated in response to hypoxia-induced stress such as in the tumor microenvironment. This study examined the role of CREB3L1 (cyclic AMP [cAMP]-responsive element-binding protein 3-like protein 1), a member of the UPR, in breast cancer development and metastasis. Initial experiments identified the loss of CREB3L1 expression in metastatic breast cancer cell lines compared to low-metastasis or nonmetastatic cell lines. When metastatic cells were transfected with CREB3L1, they demonstrated reduced invasion and migration in vitro, as well as a significantly decreased ability to survive under nonadherent or hypoxic conditions. Interestingly, in an in vivo rat mammary tumor model, not only did CREB3L1-expressing cells fail to form metastases compared to CREB3L1 null cells but regression of the primary tumors was seen in 70% of the animals as a result of impaired angiogenesis. Microarray and chromatin immunoprecipitation with microarray technology (ChIP on Chip) analyses identified changes in the expression of many genes involved in cancer development and metastasis, including a decrease in those involved in angiogenesis. These data suggest that CREB3L1 plays an important role in suppressing tumorigenesis and that loss of expression is required for the development of a metastatic phenotype.
Assuntos
Neoplasias da Mama/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/metabolismo , Proteínas do Tecido Nervoso/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Animais , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular , Feminino , Expressão Gênica , Humanos , Metástase Linfática , Invasividade Neoplásica , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Ratos , Ratos Endogâmicos F344 , TranscriptomaRESUMO
Total methanolic extracts of Saponaria vaccaria seed derived from several varieties, as well as various purified components obtained through successive chromatographic separations of total extracts were evaluated for their growth inhibitory activity in WiDr (colon), MDA-MB-231 (breast), NCI-417 (lung) and PC-3 (prostate) human cancer cells as well as the non-tumorigenic fibroblast BJ (CRL-2522) cell line using MTT colorimetric assay. Purified bisdesmosidic saponins segetoside H and I were further examined using microscopy and apoptosis assays. Bisdesmosidic saponins exhibited dose-dependent growth inhibitory and selective apoptosis-inducing activity. Growth inhibitory effects were particularly strong in a breast (MDA-MB-231) and a prostate (PC-3) cancer cell line. Total extracts exhibited a different preference being most active against a colon cancer cell line (WiDr). In a comparison of varieties, all of the total seed extracts exhibited similar dose-dependent activities, but with some variation in potency. Monodesmosidic saponins vaccarosides A and B, phenolic vaccarin, and cyclopeptide segetalin A, co-occurring seed substituents, did not exhibit activity. The non-tumorigenic fibroblast cell line BJ (CRL 2522) was growth inhibited but did not undergo apoptosis when treated with bisdesmosidic saponins at low micromolar concentrations. Saponin-rich extracts from Kochia scoparia seed and Chenopodium quinoa were also evaluated alongside Saponaria saponins but did not exhibit activity. Closely related Quillaja saponins exhibited activity but were less potent.