ABSTRACT
Ascofuranone, an isoprenoid antibiotic initially purified from a culture broth of Ascochyta viciae, has multiple anticancer effects. However, the impacts of ascofuranone on the epithelial-mesenchymal transition (EMT) and epidermal growth factor (EGF)-induced effects on human lung cancer cell lines have not been previously reported. Here, we show that ascofuranone exerts its anticancer effects by inhibiting the EGF-induced EMT and cell migration in human lung cancer cell lines. Ascofuranone significantly inhibited EGF-induced migration and invasion by lung cancer cells, and suppressed EGF-induced morphologic changes by regulating the expression of EMT-associated proteins. In addition, ascofuranone upregulated E-cadherin, and downregulated fibronectin, vimentin, Slug, Snail, and Twist. Inhibition of ERK/AKT/mTOR promoted EGF-induced E-cadherin downregulation and inhibited EGF-induced vimentin upregulation in response to ascofuranone, implying that inhibition of the EGF-induced EMT by ascofuranone was mediated by the ERK and AKT/mTOR pathways. Inhibition of c-Myc suppressed EGF-induced vimentin upregulation, suggesting the involvement of c-Myc. Collectively, these findings suggest that ascofuranone inhibits tumor growth by blocking the EGF-induced EMT through a regulatory mechanism involving ERK, AKT/mTOR, and c-Myc in lung cancer cells.
Subject(s)
Antineoplastic Agents/pharmacology , Epithelial-Mesenchymal Transition/drug effects , Lung Neoplasms/drug therapy , Sesquiterpenes/pharmacology , Cell Line, Tumor , Cell Movement/drug effects , Cell Survival/drug effects , Epidermal Growth Factor/pharmacology , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Lung Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-myc/metabolism , TOR Serine-Threonine Kinases/metabolism , Wound Healing/drug effectsABSTRACT
BACKGROUND: Practical application of hemodynamic modification analysis based on computational fluid dynamics (CFD) in intracranial aneurysms is still under study. PURPOSE: To determine the clinical applicability of virtual stenting of aneurysms by comparing the simulated results with clinical outcome of real stenting. MATERIAL AND METHODS: Three-dimensional (3D) digital subtraction angiography (DSA) images were imported to a dedicated integrated prototypic CFD platform (Siemens Healthcare GmbH) which allows all necessary steps of 3D models for CFD analysis. The results of CFD simulation with virtual implantation of a stent can be visualized in the same platform for qualitative comparisons on a color-coded volume visualization window. Five small intracranial aneurysms with and without virtual stenting were analyzed and assessed on a qualitative level. Expert rating were performed for evaluating the simulated results, and comparing those to the long-term follow-up outcomes of real stenting. RESULTS: CFD simulation after virtual stenting was feasible in five differently located aneurysms and corresponded to the long-term changes of stented aneurysms by showing alteration in flow pattern. There was no significant difference (P = 0.5) between the simulated hemodynamic changes after virtual stenting and the angiographic changes after stenting in four aneurysms except one. There was good agreement regarding the assessment of the changes by two raters (kappa = 0.657). CONCLUSION: CFD analysis using patient-specific virtual stenting of the CFD platform may be used as a simple and less time-consuming test tool predicting the involution of aneurysms after stent placement by analyzing the vector visualization of the flow changes.
