ABSTRACT
BACKGROUND: Cholangiocarcinoma (CCA) is a highly aggressive tumor with a greater risk of distant metastasis. A drug that prevents CCA development and spread is urgently needed. In this research, we investigated the effect of ß-eudesmol on the migration and invasion and epithelial-mesenchymal transformation (EMT) of the CCA cell line. MATERIALS AND METHODS: MTT and transwell assays were used to investigate the antiproliferative activity, as well as activity on cell migration and cell invasion. Real-time PCR and western blot analysis were used to investigate the expression of EMT marker genes and proteins. RESULTS: ß-eudesmol was shown to exhibit potent antiproliferative activity (IC50 92.25-185.67 µM) and to significantly reduce CCA cell migration and invasion (27.3-62.7%). At both mRNA and protein levels, it significantly up-regulated the expression of epithelial marker E-cadherin (3-3.4-fold), while down-regulated the expression of mesenchymal markers-vimentin (0.6-0.8-fold) and snail-1 (0.4-0.6-fold). Furthermore, ß-eudesmol inhibited PI3K and AKT phosphorylation (0.5-0.8-fold), while activating p38MAPK activity (1.2-3.6-fold). CONCLUSION: Altogether, the anti-metastatic activity of ß-eudesmol might be due to its suppressive effect on EMT via modulating the PI3K/AKT and p38MAPK signaling cascades.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cholangiocarcinoma/metabolism , Epithelial-Mesenchymal Transition , Humans , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Sesquiterpenes, Eudesmane , p38 Mitogen-Activated Protein KinasesABSTRACT
OBJECTIVES: The effects of atractylodin (ATD), the bioactive compound from Atractylodes lancea, on migration and autophagy status of cholangiocarcinoma cell line were investigated. METHODS: Cytotoxic activity and effects on cell migration and invasion were evaluated by MTT and trans-well assay, respectively. Autophagy and underlying molecular mechanisms were investigated using flow cytometry and western blot analysis. KEY FINDINGS: ATD regulated the activity of PI3K/AKT/mTOR and p38MAPK signalling pathways which contributed to autophagy induction. HuCCT-1 cell growth was inhibited by ATD in a time- and dose-dependent manner. ATD inhibited the migration and invasion of HuCCT1 cells in a concentration-dependent manner. It also induced autophagy in HuCCT1 cells in a time- and dose-dependent manner. The SB202190 (autophagy inducer) and 3-MA (autophagy inhibitor) significantly increased and decreased the rate of ATD-induced autophagy, respectively. The 24 h exposure of ATD inhibited the phosphorylation of phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (p38MAPK) and increased Beclin-1 expression and LC3 conversion. It also reduced p-AKT/AKT, p-mTOR/mTOR and p-p38MAPK/p38MAPK. CONCLUSIONS: ATD inhibits the proliferation and induces CCA cell autophagy via regulating PI3K/AKT/mTOR and p38MAPK signalling pathways.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Atractylodes/chemistry , Bile Duct Neoplasms/metabolism , Cholangiocarcinoma/metabolism , Furans/pharmacology , MAP Kinase Signaling System , Protein Serine-Threonine Kinases/metabolism , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis , Autophagy , Beclin-1/metabolism , Bile Duct Neoplasms/drug therapy , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/metabolism , Bile Ducts, Intrahepatic/pathology , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cholangiocarcinoma/drug therapy , Furans/therapeutic use , Humans , Microtubule-Associated Proteins/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Phosphatidylinositol 3-Kinases , Phytotherapy , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Herbal medicines are attracting the attention of researchers worldwide. ß-Eudesmol is one of the most studied and major bioactive sesquiterpenes, mainly extracted from Atractylodes lancea (Thunb) DC. rhizomes. It has potential anti-tumor and anti-angiogenic activities and is an inhibitor of tumor growth by inhibiting angiogenesis by suppressing CREB activation of the growth factor signaling pathway. It also stimulates neurite outgrowth in rat pheochromocytoma cells with activation of mitogen-activated protein kinases. It may be a promising lead compound for enhancing neural function, and it may help to explain the underlying mechanisms of neural differentiation. In this review, we summarized the currently available clinical and preclinical studies describing the therapeutic applications of ß-eudesmol.
Subject(s)
Antineoplastic Agents/pharmacology , Sesquiterpenes, Eudesmane/chemistry , Signal Transduction/drug effects , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Atractylodes/chemistry , Atractylodes/metabolism , Heme Oxygenase-1/metabolism , Mitogen-Activated Protein Kinases/metabolism , Neoplasms/drug therapy , Neoplasms/parasitology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic use , Sesquiterpenes, Eudesmane/isolation & purification , Sesquiterpenes, Eudesmane/pharmacology , Sesquiterpenes, Eudesmane/therapeutic useABSTRACT
Dengue virus (DENV) causes asymptomatic to severe life-threatening infections and affects millions of people worldwide. Autophagy, a cellular degradative pathway, has both proviral and antiviral functions. Dengue virus triggers the autophagy pathway for the successful replication of its genome. However, the exact mechanism and the viral factors involved in activating this pathway remain unclear. This review summarizes the existing knowledge on the mechanism of autophagy induction and its significance during DENV infection.
