Inhibitory effects of oligonol on phorbol ester-induced tumor promotion and COX-2 expression in mouse skin: NF-kappaB and C/EBP as potential targets.
Plant polyphenols possess anti-oxidant and anti-inflammatory activities and are hence potential candidates for preventing cancer. The present study was aimed at evaluating the anti-inflammatory and anti-tumor promoting activity of oligonol, a formulation of catechin-type oligomers, in mouse skin stimulated with a proto-type tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Pretreatment of mouse skin with oligonol significantly inhibited TPA-induced expression of cyclooxygenase-2 (COX-2). Oligonol diminished nuclear translocation and DNA binding of nuclear factor-kappaB (NF-kappaB) via blockade of phosphorylation and subsequent degradation of IkappaB alpha in TPA-treated mouse skin. Moreover, oligonol suppressed TPA-induced DNA binding of CCAAT/enhancer-binding protein (C/EBP) in mouse skin. Oligonol pretreatment also attenuated the phosphorylation and/or catalytic activities of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinase. Moreover, p38 MAP kinase inhibitor SB203580, but not the MEK inhibitor U0126, negated TPA-induced DNA binding of C/EBP. In addition, oligonol reduced the incidence and the multiplicity of papillomas and squamous cell carcinomas in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and TPA-promoted mouse skin, and prolonged the survival of tumor-bearing mice. Pretreatment with oligonol diminished the levels of proliferating cell nuclear antigen and expression of COX-2 in papillomas and carcinomas, respectively, as compared to DMBA plus TPA treatment alone. Taken together, the above findings suggest that oligonol inhibits TPA-induced COX-2 expression by blocking the activation of NF-kappaB and C/EBP via modulation of MAP kinases and suppresses chemically induced mouse skin tumorigenesis.
National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-ku, Seoul 151-742, Republic of Korea.
Joydeb Kumar
JK
Kundu
Dal-Mi
DM
Hwang
Jung-Chul
JC
Lee
Eun-Jin
EJ
Chang
Young Kee
YK
Shin
Hajime
H
Fujii
Buxiang
B
Sun
Young-Joon
YJ
Surh
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010636:Phenols / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000503:physiopathology*
D022762:CCAAT-Enhancer-Binding Proteins; D016328:NF-kappa B; D010636:Phenols; D010703:Phorbol Esters; C514283:oligonol; D002392:Catechin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2