title: Xanthoceraside induces apoptosis in melanoma cells through the activation of caspases and the suppression of the IGF-1R/Raf/MEK/ERK signaling pathway.
abstract: Xanthoceraside, a saponin extracted from the husks of Xanthoceras sorbifolia Bunge, suppresses inflammation and oxidative stress. However, the antitumor properties of xanthoceraside as well as its mechanism of action remain unclear. Therefore, we proposed to investigate its potential anticancer property. In this study, the viability of cells was measured by the MTT assay. Cell cycle and mitochondrial membrane potential were measured by flow cytometry, and the expressions of procaspase-9, procaspase-3, Cyto.c, Apaf-1, Bcl-2, Bcl-xL, Bad, p53, and IGF-1R/Raf/MEK/ERK were tested by Western blotting. Xanthoceraside significantly inhibited the proliferation of human melanoma A375.S2 cells in a concentration- and time-dependent manner but did not impair the viability of normal cells (peripheral blood mononuclear cells). Further analysis revealed that xanthoceraside induced apoptosis by activating caspase-3 and caspase-9 in a time-dependent manner through the mitochondrial pathway but did not activate caspase-8 in the cells. In addition, xanthoceraside inhibited the expression of the insulin-like growth factor-1 receptor (IGF-1R), which is an important prosurvival, antiapoptotic signaling growth factor receptor that is frequently overexpressed in cancer cells and used as a therapeutic target for multiple cancers. Interestingly, xanthoceraside also decreased the expression of Raf, p-MEK, and p-ERK, the downstream effectors of IGF-1R. Taken together, these findings indicate that xanthoceraside induces apoptosis through a mitochondria-mediated apoptotic pathway, which is induced by the downregulation of IGF-1R/Raf/MEK/ERK cascades in A375.S2 cells.
authors.affiliation: Department of Pharmacology, School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University , Shenyang, People's Republic of China .
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiao
authors.forename: Libo
authors.initials: L
authors.lastname: Zou
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Yifei
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Lu
authors.initials: L
authors.lastname: Zou
authors.forename: Tianyan
authors.initials: T
authors.lastname: Chi
authors.forename: Xuefei
authors.initials: X
authors.lastname: Ji
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D010936:Plant Extracts / Q000494:pharmacology*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D029631:Sapindaceae / Q000737:chemistry*; D012503:Saponins / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D010936:Plant Extracts; D012503:Saponins; D014315:Triterpenes; C548611:xanthoceraside; D017526:Receptor, IGF Type 1; D019908:Proto-Oncogene Proteins c-raf; D020169:Caspases
keywords: A375.S2 cells; apoptosis and signal transduction; xanthoceraside