title: Nobiletin induces apoptosis and potentiates the effects of the anticancer drug 5-fluorouracil in p53-mutated SNU-16 human gastric cancer cells.
abstract: Nobiletin is a typical polymethoxyl flavone from citrus fruits that has anticancer properties, but the molecular mechanism of its inhibitory effects on the growth of p53-mutated SNU-16 human gastric cancer cells has not been explored. In this study, nobiletin was found to be effective at inhibiting the proliferation of SNU-16 cells than other flavonoids. Nobiletin induced the death of SNU-16 cells through apoptosis, as evidenced by the increased cell population in the sub-G1 phase, the appearance of fragmented nuclei, an increase in the Bax/Bcl-2 ratio, the proteolytic activation of caspase-9, an increase in caspase-3 activity, and the degradation of poly(ADP-ribose) polymerase (PARP) protein. We found that the combination of nobiletin plus the anticancer drug 5-fluorouracil (5-FU) reduced the viability of SNU-16 cells in a concentration-dependent manner and exhibited a synergistic anticancer effect (combination index = 0.38) when 5-FU was used at relatively low concentrations. The expression of p53 protein increased after treatment with 5-FU, but not nobiletin, whereas the expression of p21 (WAF1/CIP1)  protein increased after treatment with nobiletin, but not 5-FU. The cellular responses to nobiletin and 5-FU occurred through different pathways. The results of this study suggest the potential application of nobiletin to the enhancement of 5-FU efficiency in p53 mutant tumors.
authors: Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju, Republic of Korea.
authors: Jeong Yong
authors: JY
authors: Moon
authors: Moonjae
authors: M
authors: Cho
authors: Kwang Seok
authors: KS
authors: Ahn
authors: Somi Kim
authors: SK
authors: Cho
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000008:administration & dosage / Q000494:pharmacology*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D009154:Mutation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047309:Flavones; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C008661:nobiletin; D011065:Poly(ADP-ribose) Polymerases; D053453:Caspase 9; D005472:Fluorouracil