ABSTRACT
Abnormal activation of ß-catenin has been reported in 90% in the sporadic and hereditary colorectal cancer. The suppression of abnormally activated ß-catenin is one of the good strategies for chemoprevention and treatment of colorectal cancer. In this study, we have isolated two main compounds from root of Saussurea lappa, dehydrocostus lactone (DCL) and costunolide (CL), and investigated their anti-colorectal cancer activities. DCL and CL suppressed cyclin D1 and survivin through inhibiting nuclear translocation of ß-catenin. They also suppressed the nuclear translocation of galectin-3 that is one of the coactivators of ß-catenin in SW-480 colon cancer cells. Furthermore, DCL and CL suppressed proliferation and survival of SW-480 colon cancer cells through the induction of cell cycle arrest and cell death. Taken together, DCL and CL from root of S. lappa have anti-colorectal cancer activities through inhibiting Wnt/ß-catenin pathway.
Subject(s)
Colorectal Neoplasms/pathology , Lactones/pharmacology , Sesquiterpenes/pharmacology , Wnt Signaling Pathway/drug effects , Blood Proteins , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor/drug effects , Colorectal Neoplasms/metabolism , Cyclin D1/metabolism , Galectin 3/metabolism , Galectins , Humans , Inhibitor of Apoptosis Proteins/metabolism , Plant Roots/chemistry , Saussurea/chemistry , Survivin , beta Catenin/metabolismABSTRACT
Wnt/ß-catenin signaling pathway was mutated in about 90% of the sporadic and hereditary colorectal cancers. The abnormally activated ß-catenin increases the cancer cell proliferation, differentiation and metastasis through increasing the expression of its oncogenic target genes. In this study, we identified an inhibitor of ß-catenin dependent Wnt pathway from rhizomes of Atractylodes macrocephala Koidzumi (Compositae). The active compound was purified by activity-guided purification and the structure was identified as 2,8-dimethyl-6-hydroxy-2-(4-methyl-3-pentenyl)-2H-chromene (atractylochromene, AC). AC suppressed ß-catenin/T-cell factor transcriptional activity of HEK-293 reporter cells when they were stimulated by Wnt3a or inhibitor of glycogen synthase kinase-3ß. AC down-regulated the nuclear level of ß-catenin through the suppression of galectin-3 mediated nuclear translocation of ß-catenin in SW-480 colon cancer cells. Furthermore, AC inhibits proliferation of colon cancer cell. Taken together, AC from A. macrocephala might be a potential chemotherapeutic agent for the prevention and treatment of human colon cancer.
