Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis‐promoted hepatocarcinogenesis in rats

Abstract

Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) promoted diethylnitrosamine (DEN)-initiated hepatocarcinogenesis in a rat model. Using this model, we investigated the efficacy of an equivalent dosage of dietary LY from either a pure compound or a tomato extract (TE) against NASH-promoted hepatocarcinogenesis. Six groups of rats were injected with DEN and then fed either Lieber-DeCarli control diet or HFD with or without LY or TE for 6 weeks. Results showed that both LY and TE supplementations significantly decreased the number of altered hepatic foci expressing the placental form of glutathione Stransferase in the livers of HFD-fed rats. This was associated with significantly lower proliferating cell nuclear antigen positive hepatocytes and cyclinD1 protein, as well as decreased activation of extracellular signal-regulated kinase and nuclear NF-jB. Although both LY and TE supplementations reduced HFD-induced lipid peroxidation in the livers, we observed significantly decreased cytochrome P450 2E1, inflammatory foci and mRNA expression of proinflammatory cytokines (TNF-a, IL-1b and IL-12) in the HFD1TE fed group but increased nuclear NF-E2-related factor-2 and heme oxygenase-1 proteins in the HFD1LY fed group, relative to HFD feeding alone. These data indicate that LY and TE can inhibit NASH-promoted hepatocarcinogenesis mainly as a result of reduced oxidative stress, which could be fulfilled through different mechanisms.Primary liver cancer has become the 5th commonest malignancy worldwide, accounting for 5.6% of all human cancers. 1Although surgical resection is the major therapeutic option, the lack of early detection or screening biomarkers usually leads to its diagnosis at an advanced stage. Thus, the identification of potential risk factors for early hepatocarcinogenesis and the exploration of preventive or protective measures against them at an early stage are immensely needed. Over the past decade, growing evidence has revealed a close association between hepatocellular carcinoma and nonalcoholic steatohepatitis (NASH), a chronic and progressive liver disease characterized by the concurrence of fat accumulation and infiltration of inflammatory cells in the liver.2-4 Moreover, patients with NASH have a high risk for proceeding to cirrhosis 5 and eventually hepatocellular carcinoma. Recently, we provided experimental evidence that the altered hepatic foci (AHF) expressing placental form of glutathione S-transferase (P-GST), as initiated by hepatic carcinogen diethylnitrosamine (DEN), were significantly increased in the context of high-fat diet (HFD) induced NASH,6 in which increased oxidative stress could act as a key component contributing to this preneoplastic process. Since NASH has become one of the most common causes of advanced liver diseases in both dev...

Terpenoids as potential chemopreventive and therapeutic agents in liver cancer

“…They also concluded that lycopene's chemopreventive effects were due to its modulating effect on the liver enzyme activating DENA, namely CYP2E1. Three other research groups [155,181,184] conducted their studies using several chemical hepatocarcinogenesis model and observed similar end points as Astorg et al [154] . All three research groups observed the chemopreventive effects of lycopene on hepatocellular carcinogenesis induced by DENA in rats as indicated by inhibition of GSTp foci.…”

“…All three research groups observed the chemopreventive effects of lycopene on hepatocellular carcinogenesis induced by DENA in rats as indicated by inhibition of GSTp foci. Wang et al [184] confirmed the efficacy of lycopene against nonalcoholic steatohepatitis (NASH)-promoted hepatocarcinogenesis and provided several molecular mechanisms, such as lowering of protein expression of proliferating cell nuclear antigen, cyclin D1, and NF-κB as well as induction in nuclear NF-E2 related factor-2 and heme oxygenase-1 protein expressions. The efficacy of tomato extract (TE) as a chemopreventive agent against DENA-initiated NASHpromoted hepatocarcinogenesis in male rats was also investigated.…”

“…Reduced the number of GSTp foci initiated by DENA and promoted by NASH in male Sprague-Dawley rats ↓PCNA; ↓cyclinD1; ↓TNF-α; ↓IL-1β; ↓IL-12; ↓lipid peroxidation; ↓CYP2E1; ↓pERK; ↓NF-κB 250 mg/kg per day; 6 wk Diet Wang et al [184] Sesquiterpenoids [124] Farnesol Suppressed the development of GSTp foci and nodules initiated with DENA and promoted by 2-AAF in male Wistar rats ↓cell proliferation; ↓DNA damage; ↓plasma cholesterol; ↓HMG-CoA reductase 250 mg/kg; 8 wk po Ong et al [129] Zerumbone Reduced DENA/2-AAF-induced hepatocarcinogenesis in Sprague-Dawley rats ↓ALP; ↓ALT; ↓AST; ↓AFP; ↓lipid peroxidation; ↓GSH; ↓PCNA; ↑Bax; ↓Bcl-2 15, 30 or 60 mg/kg; twice a week for 11 wk ip Taha et al [186] and similar study by Cardozo et al [130] observed the same chemopreventive benefits of geraniol in male Wistar rats initiated with DENA promoted by phenobarbital (PB). Geraniol was found to suppress liver carcinogenesis by inhibiting the promotion phase through induction of apoptosis and reduction of hepatic membrane protein RhoA.…”

The effect of tomato juice supplementation on biomarkers and gene expression related to lipid metabolism in rats with induced hepatic steatosis

“…These compounds can counteract hepatocyte injury associated with lipid peroxidation and chronic oxidative stress. Some authors have reported a positive effect of dietary antioxidants such as vitamins C and E [5,6], bioactive compounds like resveratrol [7] and lycopene [8,9], and antioxidant drugs such as N-acetylcysteine [10] on the biomarkers of NAFLD, as well as highlighting that they impede progression toward NASH in both human and animal models. Tomatoes are characterized by a low fat and protein content, and are rich in phenolic compounds, carotenoids, and vitamins C and E [11,12].…”

Chemoprevention against hepatocellular carcinoma

“…Several epidemiological and experimental studies have demonstrated beneficial effect of lycopene on preventing HCC [129][130][131]; for example, lycopene-rich diet significantly inhibited DEN-initiated and NASH-promoted early hepatocarcinogenesis in rats, which was associated with decreased expression of cyclin D1, as well as inhibition of ERK1/2 and NF-kappaB activities independently of apoptosis [132]. The accumulated literature suggests the possibility that higher consumption of tomato products or lycopene is safe and may have potential benefits for lowering the risk of cancer including HCC; however, further research is necessary to draw definitive conclusions.…”