title: Growth inhibition and apoptosis-inducing effects of cudraflavone B in human oral cancer cells via MAPK, NF-κB, and SIRT1 signaling pathway.
abstract: The goal of this study was to investigate the effect and molecular mechanism of cudraflavone B, a prenylated flavonoid isolated from the root bark of Cudrania tricuspidata, against oral squamous cell carcinoma cells. We observed that cudraflavone B inhibited proliferation of these cells in a time- and dose-dependent manner. At 15 µM, cudraflavone B induced cell death via apoptosis (characterized by the appearance of nuclear morphology) and increased the accumulation of the sub-G1 peak (portion of apoptotic annexin V positive cells). Treatment with cudraflavone B triggered the mitochondrial apoptotic pathway (indicated by induction of the proapoptotic protein p53 and the p21 and p27 effector proteins), downregulation of cell cycle regulatory proteins (e.g., p-Rb, changing Bax/Bcl-2 ratios, cytochrome-c release), and caspase-3 activation. Cudraflavone B time-dependently activated NF-κB, the MAP kinases p38, and ERK, and induced the expression of SIRT1. SIRT1 activator, resveratrol, dose-dependently attenuated the growth-inhibitory and apoptosis-inducing effect of cudraflavone B and blocked cudraflavone B-induced regulatory protein expressions in the mitochondrial pathway such as p53, p21, p27, Bax, caspase-3, and cytochrome-c. Conversely, treatment with SIRT1 inhibitor sirtinol caused opposite effects. These results demonstrate for the first time that the molecular mechanism underlying the antitumor effect in oral squamous cell carcinoma cells is related to the activation of MAPK/and NF-κB as well as of the SIRT1 pathway. Therefore, cudraflavone B may be a lead for the development of a potential candidate for human oral squamous cell carcinoma cells.
authors.affiliation: Department of Maxillofacial Tissue Regeneration and Research Center for Tooth & Periodontal Regeneration (MRC), School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Hwa-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Q-Schick
authors.initials: QS
authors.lastname: Auh
authors.forename: Young-Man
authors.initials: YM
authors.lastname: Lee
authors.forename: Soo-Kyung
authors.initials: SK
authors.lastname: Kang
authors.forename: Seok-Woo
authors.initials: SW
authors.lastname: Chang
authors.forename: Dong-Sung
authors.initials: DS
authors.lastname: Lee
authors.forename: Youn-Chul
authors.initials: YC
authors.lastname: Kim
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D029586:Moraceae / Q000737:chemistry*; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D008517:Phytotherapy; D024301:Plant Bark; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018517:Plant Roots; D011494:Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D005419:Flavonoids; D016328:NF-kappa B; D010936:Plant Extracts; C542041:cudraflavone B; D011494:Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; C447939:SIRT1 protein, human; D056564:Sirtuin 1