Chemopreventive activities of farnesol (FOH) and geraniol (GOH) were evaluated during the initial phases of hepatocarcinogenesis. Rats received during eight consecutive weeks 25 mg/100 g body weight FOH (FOH group) or GOH (GOH group), or only corn oil (CO group, controls). Incidence (%) and mean number of visible hepatocyte nodules/animal were inhibited in FOH group (13% and 4 ± 1; P < 0.05), but not in GOH group (42% and 18 ± 17, P > 0.05), compared to CO group (100% and 42 ± 17). Mean area (mm ² ) and % liver section area occupied by total hepatic placental glutathione S -transferase positive preneoplastic lesions (PNLs) were reduced in FOH group (0.09 ± 0.06; 2.8 ± 1.3; P < 0.05) compared to CO group (0.18 ± 0.12; 10.0 ± 2.8), while in GOH group only the mean area of these PNL was reduced (0.11 ± 0.09; P < 0.05), but not the % liver section area occupied by them (5.1 ± 1.1; P > 0.05). Compared to CO group, FOH and GOH groups showed reduced ( P < 0.05) PNL cell proliferation and DNA damage, but only GOH group showed increased PNL apoptosis ( P < 0.05). FOH group, but not GOH group, presented reduced ( P < 0.05) total plasma cholesterol levels and increased ( P < 0.05) hepatic levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase mRNA, compared to CO group. No differences ( P > 0.05) were observed between CO, FOH and GOH regarding hepatic levels of farnesoid X activated receptor (FXR) protein. Results indicate that FOH and GOH could represent promising chemopreventive agents against hepatocarcinogenesis. Inhibition of cell proliferation and DNA damage relate to both isoprenoids' anticarcinogenic actions while induction of apoptosis specifically relates to GOH protective actions. Inhibition of HMGCoA reductase activity could be associated with FOH, but not GOH anticarcinogenic actions. FXR does not seem to be involved in the isoprenoids' chemopreventive activities.

Bioactive food compounds (BFCs) exhibit potential anticarcinogenic effects that deserve to be explored. Butyric acid (BA) is considered a promising BFC and has been used in clinical trials; however, its short half-life considerably restricts its therapeutic application. Tributyrin (TB), a BA prodrug present in milk fat and honey, has more favorable pharmacokinetic properties than BA, and its oral administration is also better tolerated. In vitro and in vivo studies have shown that TB acts on multiple anticancer cellular and molecular targets without affecting non-cancerous cells. Among the TB mechanisms of action, the induction of apoptosis and cell differentiation and the modulation of epigenetic mechanisms are notable. Due to its anticarcinogenic potential, strategies as lipid emulsions, nanoparticles, or structured lipids containing TB are currently being developed to improve its organoleptic characteristics and bioavailability. In addition, TB has minimal toxicity, making it an excellent candidate for combination therapy with other agents for the control of cancer. Despite the lack of data available in the literature, TB is a promising molecule for anticancer strategies. Therefore, additional preclinical and clinical studies should be performed using TB to elucidate its molecular targets and anticarcinogenic potential.

Chemopreventive activities of the isoprenoids geranylgeraniol (GGO) and β-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 (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-κB) 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-κB activation seems to be specifically related to GGO actions.

The reversibility of non-genotoxic phenotypic alterations has been explored in order to develop novel preventive and therapeutic approaches for cancer control. Previously, it has been demonstrated that histone deacetylase (HDAC) inhibitor tributyrin, a butyric acid prodrug, to have chemopreventive effects on rat hepatocarcinogenesis. The goal of this study was to determine molecular mechanisms associated with the chemopreventive activity of tributyrin. Male Wistar rats were allocated randomly to untreated control group and two experimental groups. Rats in the experimental group 1 were treated with maltodextrin (3g/kg body wt), and rats in experimental group 2 were treated with tributyrin (2g/kg body wt) daily for 8 weeks. Two weeks after treatment initiation, rats from experimental groups were subjected to a ‘resistant hepatocyte’ model of hepatocarcinogenesis. Treatment with tributyrin resulted in lower HDAC activity and Hdac3 and Hdac4 gene expression, and an increase of histone H3 lysine 9 and 18 and histone H4 lysine 16 acetylation as compared with the experimental group 1. In addition to the increase in histone acetylation, tributyrin caused an increase in the acetylation of the nuclear p53 protein. These changes were accompanied by a normalization of the p53-signaling network, particularly by the upregulation of pro-apoptotic genes, and a consequent increase of apoptosis and autophagy in the livers of tributyrin-treated rats. These results indicate that the chemopreventive activity of tributyrin may be related to an increase of histone and p53 acetylation, which could lead to the induction of the p53 apoptotic pathway.