Carcinogenesis Advance Access originally published online on February 17, 2005
Carcinogenesis 2005 26(6):1091-1099; doi:10.1093/carcin/bgi047
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Carcinogenesis vol.26 no.6 © Oxford University Press 2005; all rights reserved.
Geranylgeraniol and ß-ionone inhibit hepatic preneoplastic lesions, cell proliferation, total plasma cholesterol and DNA damage during the initial phases of hepatocarcinogenesis, but only the former inhibits NF-
B activation
Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil
* To whom correspondence should be addressed: Departamento de Alimentos e Nutrição Experimental, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Bloco 14, Av. Prof. Lineu Prestes 580, 05508-900, São Paulo, SP, Brazil. Tel: 55 11 3091 3630; Fax: 55 11 3815 4410; Email: RMORENO{at}USP.BR
Chemopreventive activities of the isoprenoids geranylgeraniol (GGO) and ß-ionone (BI) were evaluated during initial phases of hepatocarcinogenesis. Rats received 8 or 16 mg/100 g body wt GGO (GGO8 and GGO16 groups) or BI (BI8 and BI16 groups), or only corn oil (CO group, controls) daily for 7 weeks. Incidence (%) and the mean number of visible hepatocyte nodules/animal were inhibited in the GGO8 (64% and 21 ± 40), GGO16 (33% and 3 ± 5), BI8 (50% and 13 ± 34) and BI16 (42% and 9 ± 19) groups compared with the CO group (100% and 34 ± 51) (P < 0.05, except for the GGO8 group). Number/cm2 liver section, mean area (mm2) and % liver section area occupied by persistent hepatic placental glutathione S-transferase positive preneoplastic lesions (PNL) were reduced in the GGO8 (11 ± 9; 0.26 ± 0.35; 2.7 ± 3.0), GGO16 (6 ± 6; 0.18 ± 0.16; 0.9 ± 0.9), BI8 (9 ± 5; 0.13 ± 0.20; 1.1 ± 1.2) and BI16 (8 ± 6; 0.08 ± 0.09; 0.6 ± 0.4) groups compared with the CO group (26 ± 18; 0.29 ± 0.34; 7.0 ± 5.5) (P < 0.05). GGO16 and BI16 groups showed smaller visible hepatocyte nodules, reduced PNL cell proliferation and total plasma cholesterol levels compared with the CO group (P < 0.05), but did not show any differences (P > 0.05) in PNL apoptosis. DNA damage expressed as comet length (µm) was reduced in the GGO8 (96.7 ± 1.5), GGO16 (94.2 ± 1.5), BI8 (97.1 ± 1.1) and BI16 (95.1 ± 1.5) groups compared with the CO group (102.1 ± 1.7) (P < 0.05). In comparison with normal animals, the CO group animals showed increased (P < 0.05) nuclear levels of nuclear factor kappa B (NF-
B) p65 subunit in hepatic cells, which were decreased (P < 0.05) in the GGO16 group animals. Anticarcinogenic actions of these isoprenoids seem to follow a dose–response relationship. Results indicate that GGO and BI could be represented as promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage seems to be important for the anticarcinogenic actions of isoprenoids, while the inhibition of NF-B activation seems to be specifically related to GGO actions.
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