title: Flavonoids isolated from Citrus platymamma induce mitochondrial-dependent apoptosis in AGS cells by modulation of the PI3K/AKT and MAPK pathways.
abstract: Citrus platymamma hort. ex Tanaka (Rutaceae family) has been widely used in Korean folk medicine for its wide range of medicinal benefits including an anticancer effect. In the present study, we aimed to investigate the molecular mechanism of the anticancer effects of flavonoids isolated from Citrus platymamma (FCP) on AGS cells. FCP treatment significantly inhibited AGS cell growth in a dose‑dependent manner. Furthermore, FCP significantly increased the percentage of cells in the sub-G1 phase (apoptotic cell population), and apoptosis was confirmed by Annexin V double staining. Chromatin condensation and apoptotic bodies were also noted in the FCP-treated AGS cells. Moreover, immunoblotting results showed that FCP treatment significantly decreased the expression of procaspase-3, -6, -8 and -9, and PARP and increased cleaved caspase-3, cleaved PARP and the Bax/Bcl-xL ratio in a dose-dependent manner. In addition, the phosphorylation of AKT was significantly decreased, whereas extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) were significantly increased in the FCP-treated AGS cells. Taken together, the cell death of AGS cells in response to FCP was mitochondrial-dependent via modulation of the PI3K/AKT and MAPK pathways. These findings provide new insight for understanding the mechanism of the anticancer effects of FCP. Thus, FCP may be a potential chemotherapeutic agent for the treatment of gastric cancer.
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Jinju, Gyeongsang 660-701, Republic of Korea.
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongsang 660-702, Republic of Korea.
authors.forename: Arulkumar
authors.initials: A
authors.lastname: Nagappan
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Jinju, Gyeongsang 660-701, Republic of Korea.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Park
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Jinju, Gyeongsang 660-701, Republic of Korea.
authors.forename: Gyeong Eun
authors.initials: GE
authors.lastname: Hong
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Jinju, Gyeongsang 660-701, Republic of Korea.
authors.forename: Silvia
authors.initials: S
authors.lastname: Yumnam
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Jinju, Gyeongsang 660-701, Republic of Korea.
authors.forename: Suchismita
authors.initials: S
authors.lastname: Raha
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Jinju, Gyeongsang 660-701, Republic of Korea.
authors.forename: Venu Venkatarame Gowda
authors.initials: VV
authors.lastname: Saralamma
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Gyeongsang 660-702, Republic of Korea.
authors.forename: Won Sup
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Nursing Science, International University of Korea, Jinju, Gyeongsang 660-759, Republic of Korea.
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine (BK21 Plus Project), Gyeongsang National University, Jinju, Gyeongsang 660-701, Republic of Korea.
authors.forename: Gon Sup
authors.initials: GS
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002957:Citrus / Q000737:chemistry; D005419:Flavonoids / Q000008:administration & dosage* / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D051058:Oncogene Protein v-akt / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D005419:Flavonoids; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D020929:Mitogen-Activated Protein Kinase Kinases