Geranylgeraniol and beta-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-kappaB activation.
Chemopreventive activities of the isoprenoids geranylgeraniol (GGO) and beta-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/cm(2) liver section, mean area (mm(2)) 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 (microm) 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-kappaB) 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-kappaB activation seems to be specifically related to GGO actions.
de Moura Espíndola
Roseli
R
Laboratory of Diet, Nutrition and Cancer, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Mazzantini
Rogério Pietro
RP
Ong
Thomas Prates
TP
de Conti
Aline
A
Heidor
Renato
R
Moreno
Fernando Salvador
FS
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D003314:Corn Oil; D004249:DNA Damage / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045792:Norisoprenoids / Q000494:pharmacology*; D011230:Precancerous Conditions / Q000473:pathology / Q000517:prevention & control; D051381:Rats; D017208:Rats, Wistar; D051996:Transcription Factor RelA
D016588:Anticarcinogenic Agents; D004224:Diterpenes; D016328:NF-kappa B; D045792:Norisoprenoids; D051996:Transcription Factor RelA; D003314:Corn Oil; D002784:Cholesterol; C008157:beta-ionone; C017338:geranylgeraniol