title: Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways.
abstract: Tangeretin, a natural polymethoxyflavone present in citrus peel oil, is known to have anticancer activities in breast cancer, colorectal carcinoma and lung carcinoma, yet, the underlying mechanisms of tangeretin in human gastric cancer AGS cells have not been investigated to date. In the present study, the apoptotic mechanisms of tangeretin in AGS cells were explored. It was observed that tangeretin increased the apoptotic rates of AGS cells following treatment with tangeretin for 48 h in a dose-dependent manner by Annexin V-FITC and PI double staining. In addition, characteristic apoptotic morphology such as nuclear shrinkage and apoptotic bodies was observed after Hoechst 33258 staining. Flow cytometric assay showed that treatment of AGS cells with tangeretin decreased the mitochondrial membrane potential (MMP) in a dose-dependent manner, which indicated that mitochondrial dysfunction was involved in the tangeretin-induced apoptosis. Caspase-3, -8 and -9 activities were increased by tangeretin in a dose-dependent manner. Western blotting showed that the protein levels of pro-apoptotic proteins including cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax, Bid, tBid, p53, p21/cip1, Fas and FasL were significantly upregulated by tangeretin. In addition, PFT-α (a p53 inhibitor) reduced the apoptotic rates and the expression of p53, p21, caspase-3 and caspase-9 induced by tangeretin, indicating that tangeretin-induced apoptosis was p53-dependent. In conclusion, these results suggest that tangeretin induces the apoptosis of AGS cells mainly through p53-dependent mitochondrial dysfunction and the Fas/FasL-mediated extrinsic pathway.
authors.affiliation: Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Aili
authors.initials: A
authors.lastname: Cao
authors.affiliation: Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Shi
authors.affiliation: Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Peihao
authors.initials: P
authors.lastname: Yin
authors.affiliation: Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ji
authors.affiliation: Institute of Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Jianqun
authors.initials: J
authors.lastname: Xie
authors.affiliation: Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China.
authors.forename: Dazheng
authors.initials: D
authors.lastname: Wu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047309:Flavones / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D047309:Flavones; C059006:tangeretin