Dietary intake of pterostilbene, a constituent of blueberries, inhibits the beta-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats.
Stilbenes are phytochemicals present in grapes, berries, peanuts and red wine. A widely studied stilbene, resveratrol (trans-3,5,4'-trihydroxystilbene), has been shown to exert antioxidant, anti-inflammatory, chemopreventive and antiaging effects in a number of biological systems. We reported earlier that pterostilbene (trans-3,5-dimethoxy-4'-hydroxystilbene), a structurally related stilbene found in blueberries, was effective in reducing the incidence and multiplicity of aberrant crypt foci formation in the colon of rats injected with azoxymethane (AOM). Our present study was to identify the chemopreventive potential of pterostilbene with colonic tumor formation as an end point and further to evaluate the mechanistic action of pterostilbene during colon carcinogenesis. F344 rats were given two AOM injections subcutaneously when they were 7 and 8 weeks old and continuously fed the control or 40 p.p.m. pterostilbene diet for 45 weeks. Overall analyses indicated that pterostilbene reduced colon tumor multiplicity of non-invasive adenocarcinomas, lowered proliferating cell nuclear antigen and downregulated the expression of beta-catenin and cyclin D1. Pterostilbene decreased mucosal levels of the proinflammatory cytokines, tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-4. Colon tumors from pterostilbene-fed animals showed reduced expression of inflammatory markers as well as nuclear staining for phospho-p65, a key molecule in the nuclear factor-kappaB pathway. In HT-29 cells, pterostilbene reduced the protein levels of beta-catenin, cyclin D1 and c-MYC, altered the cellular localization of beta-catenin and inhibited the phosphorylation of p65. Our data with pterostilbene in suppressing colon tumorigenesis, cell proliferation as well as key inflammatory markers in vivo and in vitro suggest the potential use of pterostilbene for colon cancer prevention.
Paul
Shiby
S
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854, USA.
DeCastro
Andrew J
AJ
Lee
Hong Jin
HJ
Smolarek
Amanda K
AK
So
Jae Young
JY
Simi
Barbara
B
Wang
Chung Xiou
CX
Zhou
Renping
R
Rimando
Agnes M
AM
Suh
Nanjoo
N
D000818:Animals; D001397:Azoxymethane; D003110:Colonic Neoplasms / Q000517:prevention & control*; D019938:Cyclin D1 / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000032:analysis; D016207:Cytokines / Q000032:analysis / Q000037:antagonists & inhibitors; D019073:HT29 Cells; D006801:Humans; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects*; D013267:Stilbenes / Q000008:administration & dosage*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000502:physiology; D051176:beta Catenin / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
D016207:Cytokines; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D013267:Stilbenes; D051996:Transcription Factor RelA; D051176:beta Catenin; D019938:Cyclin D1; C107773:pterostilbene; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D001397:Azoxymethane