Research articleChemopreventive effects of β-ionone and geraniol during rat hepatocarcinogenesis promotion: distinct actions on cell proliferation, apoptosis, HMGCoA reductase, and RhoA
Introduction
The consumption of bioactive compounds in food has been previously demonstrated to correlate with reduction in cancer risk [1]. Dietary isoprenic derivatives such as β-ionone (βI), a cyclic isoprenoid present in grapes and wine [2], and geraniol (GOH), an acyclic monoterpene present in lemon and lemongrass [3], represent a promising class of chemopreventive agents [4].
The anticarcinogenic actions of βI and GOH have been described mostly in vitro [5]. Among the few in vivo studies, βI inhibits melanoma [6], breast cancer [7], and colon [8] cancer development, while GOH inhibits growth of pancreatic adenocarcinomas [9]. Both isoprenoids inhibit hepatic preneoplastic lesions (PNLs) when administered continuously during the initiation and selection/promotion phases of hepatocarcinogenesis [10], [11].
One proposed chemopreventive mechanism of isoprenoids is the suppression of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase activity, which is frequently increased and deregulated in preneoplastic and neoplastic tissues [5]. This suppression limits farnesyl and geranylgeranyl pyrophosphates [12], which are important for prenylation of proto-oncogenes such as RhoA [12], [13], thereby inhibiting cell proliferation and inducing apoptosis [14], [15], [16].
In the present study, the chemopreventive activities of βI and GOH were investigated when administered during the promotion phase of the “resistant hepatocyte” (RH) model of hepatocarcinogenesis. Parameters that were evaluated include PNL development, cell proliferation, apoptosis, total plasma cholesterol concentration, HMGCoA reductase mRNA levels, RhoA activation, and hepatic concentrations of βI and GOH.
Section snippets
Chemicals
βI [4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3(E)-buten-2-one, 95%], GOH (trans-3,7-dimethyl-2, 6-octadien-1-ol, 98%), 2-acetylaminofluorene (2-AAF), 5-bromo-2′-deoxyuridine (BrdU), diethylnitrosamine (DEN), and 3,3′-diaminobenzidine were purchased from Sigma (St. Louis, MO, USA); commercial diet was purchased from Purina (Campinas, Brazil); corn oil (CO), Mazola (São Paulo, Brazil); polyclonal anti-placental glutathione S-transferase (GST-P) rabbit antibody was purchased from Medical and
Body and liver weights, incidence and mean number of visible hepatocyte nodules
Table 1 presents the data on body and liver weights and incidence and mean number per rat of visible hepatocyte nodules. No differences (P>.05) were observed between the different experimental groups regarding the final body weights and absolute and relative liver weights, which indicates that βI and GOH did not cause toxicity at the dosages that were used. Additionally, no differences (P>.05) were observed between the different experimental groups regarding incidence of nodules. When compared
Discussion
Previous studies have demonstrated the chemopreventive activity of βI [10] and GOH [11] when administered continuously during the initiation and selection/promotion phases of the RH model of hepatocarcinogenesis. Due to the experimental design of these studies, the observed protective effects were attributed to the isoprenoid-mediated modulation of carcinogen metabolism. Since reducing the initiation phase to a zero level is impossible, the most effective intervention would be at the promotion
Acknowledgments
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors are indebted to Miss Silvania M.P. Neves for providing the care and maintenance of the animals.
References (37)
Nutrition and cancer: essential elements for a roadmap
Cancer Lett
(2008)- et al.
Regulation of HMG-CoA reductase activity in plants
J Lipid Res
(1994) - et al.
Geraniol and beta-ionone inhibit proliferation, cell cycle progression, and cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells independent of effects on HMG-CoA reductase activity
Biochem Pharmacol
(2004) - et al.
Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo
J Nutr
(1997) - et al.
Inhibition of cell proliferation, induction of apoptosis, reactivation of DLC1, and modulation of other gene expression by dietary flavone in breast cancer cell lines
Cancer Detect Prev
(2007) - et al.
RhoA/Rho kinase up-regulate Bax to activate a mitochondrial death pathway and induce cardiomyocyte apoptosis
J Biol Chem
(2007) - et al.
Farnesyl anthranilate suppresses the growth, in vitro and in vivo, of murine B16 melanomas
Cancer Lett
(2000) - et al.
Modulation of hypercholesterolemia-induced alterations in apolipoprotein B and HMG-CoA reductase expression by selenium supplementation
Chem Biol Interact
(2006) The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy
Biomed Pharmacother
(2005)- et al.
Cholesterol synthesis and HMGCoA reductase activity during hepatocarcinogenesis in rats
Int J Biochem
(1986)
Effect of beta-carotene on the expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase in rat liver
Cancer Lett
Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression by sterols and nonsterols in rat liver
Arch Biochem Biophys
Rho GTPases in hepatocellular carcinoma
Biochem Biophys Acta
Geraniol, a component of plant essential oils, inhibits growth and polyamine biosynthesis in human colon cancer
J Pharmacol Exp Ther
Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention
Exp Biol Med
Beta-ionone suppresses mammary carcinogenesis, proliferative activity and induces apoptosis in the mammary gland of the Sprague-Dawley rat
Int J Cancer
Beta-ionone inhibits colonic aberrant crypt foci formation in rats, suppresses cell growth, and induces retinoid X receptor-alpha in human colon cancer cells
Mol Cancer Ther
Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol
Lipids
Cited by (60)
Determination of the volatile chemical profile of Momordica charantia (bitter melon) leaf and fruit by GC-MS
2024, Natural Product ResearchReview of anticancer activity of monoterpenoids: Geraniol, nerol, geranial and neral
2022, Chemico-Biological InteractionsCitation Excerpt :Oral treatment with geraniol of the DEN (diethylnitrosamine)-induced hepatocarcinogenic rats (Winstar Rats) significantly decreased serum transaminase levels and tumor formation of the liver, suggesting an anti-carcinogenic effect of the monoterpene [78]. A lower expression of the RhoA protein in the hepatic membranes [79], reductions of the mean area of pre-neoplastic lesions, and an increase in cellular apoptosis, from which there were decreases in tumor proliferation and DNA damage, were also observed [79,80]. Other in vivo research in which Morris hepatoma 7777 cells were implanted in mice showed that using geraniol reduced tumor growth [81].
Geraniol protects against cyclophosphamide-induced hepatotoxicity in rats: Possible role of MAPK and PPAR-γ signaling pathways
2020, Food and Chemical ToxicologyCitation Excerpt :This molecule is characterized by having multi-biological effects including antioxidant (Tiwari and Kakkar, 2009), anti-inflammatory (Nadjib Boukhatem et al., 2013), anticancer (Cho et al., 2016; Madankumar et al., 2013), antifungal (Mesa-Arango et al., 2009) and anti-ulcer effects (de Carvalho et al., 2014). Moreover, GOH has hepatoprotective (Cardozo et al., 2011; Chen et al., 2016; Ozkaya et al., 2017) and liver regenerating effects (Canbek et al., 2017; Ceyhan and Canbek, 2017). However, the effect of geraniol on CP-mediated liver injury has not been investigated.
Induction of oxidative stress as a possible mechanism by which geraniol affects the proliferation of human A549 and HepG2 tumor cells
2020, Chemico-Biological InteractionsCitation Excerpt :Its ability to sensitize tumor cells subjected to chemotherapeutic agents has been studied [16,23]. Also, there is some evidence that GOH induces apoptosis in tumor cells [7,17,21,24,25], although the mechanisms leading to cell death have not yet been clearly elucidated. Chemotherapeutic-induced oxidative stress is known to be crucial for their efficacy, as they increase ROS to cytotoxic levels, inducing selective killing of cancer cells [5].
β-ionone inhibits nonalcoholic fatty liver disease and its association with hepatocarcinogenesis in male Wistar rats
2019, Chemico-Biological InteractionsEpigenetic Aspects of Hepatocellular Carcinoma Chemoprevention
2018, Epigenetics of Cancer Prevention