RESUMO
The transcriptional repressor Snail trriggers epithelial-mesenchymal transition (EMT), the process allowing cancer cells with invasive and metastasis properties. In this study, we screened medicinal plants for the Snail inhibitory active components by high content screen (HCS) and found that the crude extract of Xylopia vielana leaves showed potential activity. Subsequently, bioassay-guided isolation of the extract of Xylopia vielana was performed to obtain twenty-four dimeric guaianes (1-24), including 16 new analogues (1-5, 8-11, 13-15, 17, 18, 21, and 22). Their structures were elucidated by the comprehensive application of multiple spectroscopic methods. Compounds 1, 11, 12, and 16 were initially identified as the active compounds. Wound healing assay, transwell migration assay and western blot experiments verified that compounds 1 and 12 inhibited the expression of Snail in a concentration-dependent manner, and compound 12 was verified as a potent tumor migration inhibitory agent. This work showed a practical strategy for the discovery of new Snail inhibitors from natural products and provided potential insights for dimeric guaianes as anticancer lead compounds specifically targeting Snail protein.
Assuntos
Plantas Medicinais/química , Sesquiterpenos de Guaiano/farmacologia , Fatores de Transcrição da Família Snail/antagonistas & inibidores , Xylopia/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Folhas de Planta/química , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/isolamento & purificação , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
The down-regulation of eukaryotic elongation factor-2 kinase (eEF2K) is associated with an enhancement in the sensitivity of malignant cells to chemotherapeutic agents. In this study, we found that the silencing of eEF2K enhanced cisplatin (CDDP)-induced cytotoxicity in CDDP-sensitive (HepG2) and resistant (HepG2/CDDP) cells. Calyxin Y, a unique chalcone diarylheptanoid adduct, down-regulated eEF2K by promoting Skp1-Cul1-F-box protein (SCF) ß-transducin repeat-containing protein (ßTrCP)-mediated protein degradation and synergistically enhanced the cytotoxicity of CDDP. Subsequently, we identified a potential mechanism of this cooperative interaction by showing that the combination of calyxin Y and CDDP enhanced apoptotic cell death via mitochondrial dysfunction. In addition, the combination induced autophagy, which contributed to the synergistic cytotoxic effect. Further research revealed that calyxin Y synergistically sensitized HepG2 and HepG2/CDDP cells to CDDP through enhanced apoptotic and autophagic cell death via the SCF ßTrCP-eEF2K pathway. Finally, in vivo studies demonstrated that calyxin Y could enhance the response of HepG2/CDDP cells to CDDP in xenograft models with low systemic toxicity. Thus, the combination of calyxin Y and CDDP might represent an attractive therapeutic strategy for the treatment of chemotherapy-sensitive and resistant hepatocellular carcinoma cells.
RESUMO
Citrifurans A-D (1-4), metabolized by an Aspergillus sp., are unusual dimers of azaphilone and furanone derivatives. Michael addition was thought to be the pivotal procedure in their biosynthesis, and different addition sites generated two new different carbon skeletons. Their structures were elucidated on the basis of spectroscopic methods, single-crystal X-ray diffraction, chemical conversion, and electronic circular dichroism analyses. Compounds 1-3 showed moderate inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages with IC50 values of 18.3, 22.6, and 25.3 µM, respectively.
Assuntos
Aspergillus/metabolismo , Furanos/química , Policetídeos/química , Animais , Benzopiranos/química , Sobrevivência Celular , Dimerização , Furanos/isolamento & purificação , Furanos/farmacologia , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/biossíntese , Pigmentos Biológicos/química , Policetídeos/isolamento & purificação , Policetídeos/farmacologia , Células RAW 264.7RESUMO
Walsuronoid B is a limonoid compound extracted from Walsura robusta. Previous studies have shown that limonoid compounds possess anti-cancer potential, although the molecular mechanism of this activity remains elusive. In this study, we demonstrated for the first time that walsuronoid B inhibited cell proliferation in several human cancer lines. Liver cancer cells (HepG2 and Bel-7402) were chosen for their high sensitivity to walsuronoid B. Walsuronoid B induced cell death through G2/M phase arrest and apoptosis and induced the accumulation of autophagosomes through the suppression of mTOR signaling, which serves as a cell survival mechanism and prevents cell death. We further examined the molecular mechanisms and found that walsuronoid B-induced dysfunction of the mitochondria and lysosomes rather than the endoplasmic reticulum contributed to its cell death effect. Walsuronoid B enhanced the generation of hydrogen peroxide, nitric oxide and superoxide anion radical, resulting in elevated levels of reactive oxygen species (ROS). In addition, ROS induced by walsuronoid B upregulated p53 levels; conversely, p53 stimulated ROS. These results suggested that ROS and p53 reciprocally promoted each other's production and cooperated to induce liver cancer cell death. We found that the induction of ROS and p53 significantly triggered G2/M phase arrest and mitochondrial and lysosomal apoptosis. Finally, walsuronoid B suppressed tumor growth in vivo with few side effects. In summary, our findings demonstrated that walsuronoid B caused G2/M phase arrest and induced mitochondrial and lysosomal apoptosis through the ROS/p53 signaling pathway in human liver cancer cells in vitro and in vivo.