Hepatocarcinogenesis In Rats Research Articles

Acyclic retinoid and angiotensin-II receptor blocker exert a combined protective effect against diethylnitrosamine-induced hepatocarcinogenesis in diabetic OLETF rats

BackgroundInsulin resistance (IR) is closely associated with the progression of hepatocellular carcinoma (HCC). Acyclic retinoid (ACR) targets retinoid X receptor α and reportedly prevents HCC recurrence in clinical practice. Angiotensin-II receptor blocker (ARB) can also inhibit experimental hepatocarcinogenesis and HCC development. These are reported to suppress IR-based hepatocarcinogenesis; however, limited data are available regarding the combined effects of both these agents. This study aimed to investigate the combined chemopreventive effect of ACR and ARB on liver tumorigenesis on rats with congenital diabetes.MethodsMale diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats underwent 70% partial hepatectomy following a single intraperitoneal injection of diethylnitrosamine to induce hepatocarcinogenesis and the administration of ACR (peretinoin, 40 mg/kg/day), ARB (losartan, 30 mg/kg/day), and a combination of ACR and ARB. Six weeks thereafter, we assessed the size and number of the pre-neoplastic lesions (PNL) as well as the altered angiogenesis, oxidative stress, and chronic inflammation in the liver. Moreover, we assessed the effects exerted by ACR and ARB on in vitro cell growth in human HCC cell lines and human umbilical vascular endothelial cells (HUVECs).ResultsOLETF rats showed increase in the size and number of PNLs compared to LETO rats. ACR suppressed the augmentation in size and number of PNLs in the OLETF rats with suppression of cell growth, intrahepatic angiogenesis, lipid peroxidation, oxidative DNA damage, and proinflammatory cytokine production. Combining ACR with ARB enhanced the tumor-suppressive effect and ameliorated intrahepatic angiogenesis, lipid peroxidation, and proinflammatory status; however, cell growth and oxidative DNA damage remained unchanged. IR-mimetic condition accelerated in vitro proliferative activity in human HCC cells, while ACR inhibited this proliferation with G0/G1 arrest and apoptosis. Furthermore, ACR and ARB significantly attenuated the HUVECs proliferation and tubular formation under the IR-mimetic condition, and a combination of both agents demonstrated greater inhibitory effects on HUVEC growth than each single treatment.ConclusionsACR and ARB exert a combined inhibitory effect against IR-based hepatocarcinogenesis by the inhibition of cell growth, intrahepatic angiogenesis, and oxidative stress. Thus, this combination therapy appears to hold potential as a chemopreventive treatment therapy against HCC.

Protective role of fucoxanthin in diethylnitrosamine-induced hepatocarcinogenesis in experimental adult rats.

Hepatocellular carcinoma (HCC) accounts for majority of cancer related deaths. Two major risk factors in induction of HCC are chemical and virus, however, the possible mechanisms of their differences remain indefinable. The current study focused on protective role of Fucoxanthin (Fx) in liver affected by diethylnitrosamine (DEN)-induced HCC. In this study, levels of liver enzymes, oxidative stressors, antioxidant status, and lipoproteins were compared both in tissue and blood. Tissues were also analyzed extensively by histological studies using H and E staining and transmission electron microscopy (TEM). Rats were clustered into four groups of six experimental animals. Group I: Control rats were administered isotonic saline intraperitoneal Group II: Animals received 0.01% DEN through drinking water to induce hepatocellular carcinoma. Group III: Animals received 0.01% DEN simultaneously oral supplementation of Fx (50 mg/kg b.w). Group IV: Rats were given Fx alone (50 mg/kg b.w) orally and the treatment is for 15 weeks. Results showed the decrease in body weight, serum albumin, antioxidant enzymes, and increased all the liver enzymes, serum bilirubin, and stress markers in DEN induced rats, where as the simultaneous supplementation of Fx reverted them to normal levels. Administration of only Fx did not show any change. Therefore, Fx may serve as a chemotherapeutic agent against liver cancer.

Olive fruit (Olea europaea L.): Chemopreventive effect in the rat model of hepatocellular carcinoma

Primary liver cancer or hepatocellular carcinoma (HCC) is an aggressive tumor with poor prognosis. Olea europaea L. commonly called olive contains diverse phytochemical constituents that have preventive effects against different diseases. The purpose of this investigation was to study the chemopreventive effect of aqueous extract of Olea europaea L. (AOE) against diethylnitrosamine (DEN)-induced HCC in rats. Olive-treated rats were pretreated with AOE intragastrically at three different doses two weeks prior to DEN injection that continued until 8 weeks. At three different time points, blood samples were collected for biochemical analysis. In the present investigation, a significant decrease in serum biomarkers of liver damage and cancer, including alfa-fetoprotein (AFP), gamma glutamyl transpeptidase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) were observed in AOE supplemented animals when compared to DEN-treated rats. In addition, AOE counteracted DEN-induced hepatic oxidative stress in rats illustrated by the restoration of reduced glutathione (GSH) and the reduction of lipid peroxidation in HCC rats. Furthermore, AOE prevented increase of relative liver weight as a prognostic marker in HCC. Finally, histopathological investigation in the liver sections confirmed the preventive effect of AOE against DEN-induced HCC. To conclude, olive has a preventive effect against DEN-induced hepatocarcinogenesis in rats.

Abnormal expression of HMGB-3 is significantly associated with malignant transformation of hepatocytes.

AIMTo explore the relationship between dynamic expression of high mobility group box-3 (HMGB3) and malignant transformation of hepatocytes.METHODSExpression of HMGB family proteins were observed in rat hepatocarcinogenesis models induced with 2-acetylaminofluorene. Alterations of HMGB3 were analyzed at the mRNA level by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and at the protein level by immunohistochemistry or Western blotting. HMGB3 in human liver cancer tissues were evaluated using bioinformatics databases from GEO, TCGA, and Oncomine. A specific HMGB3-shRNA was used to knock down HMGB3 expression in order to investigate its effects on proliferation and cell cycle in vitro and in vivo.RESULTSElevated HMGB3 levels were first reported in hepatocarcinogenesis, with increasing expression from normal liver to cancer. Bioinformatic databases showed that HMGB3 expression in hepatocellular carcinoma tissues was significantly higher than that in normal liver tissues. Higher HMGB3 expression was discovered in liver cancer cells compared with LO2 cells in vitro. According to gene set enrichment analysis, HMGB3 mRNA levels were correlated with cell cycle and DNA replication pathways. Knocking down HMGB3 by specific shRNA significantly inhibited proliferation of HepG2 cells by cell cycle arrest and downregulating DNA replication related genes (cyclin B1, FEN1, and PCNA) at the mRNA and protein level. Furthermore, silencing HMGB3 significantly inhibited xenograft tumor growth (measured by Ki67) in vivo.CONCLUSIONHMGB3 is involved in malignant transformation of hepatocytes and could be a useful biomarker for diagnosis and a potential target for therapy of liver cancer.

From hepatofibrosis to hepatocarcinogenesis: Higher cytochrome P450 2E1 activity is a potential risk factor.

Hepatofibrosis is an important susceptibility factor for hepatocarcinogenesis. However, only a handful of cases of hepatofibrosis will develop into hepatocellular carcinoma (HCC). As cytochrome P450 2E1 (CYP2E1) is involved in the metabolism and activation of many known environmental toxicants and procarcinogens, this enzyme may play a role in the development of hepatocarcinogenesis subsequent to hepatofibrosis. Herein, we evaluated whether higher CYP2E1 activity is a risk factor for the development of hepatocarcinogenesis from hepatofibrosis. CYP2E1 activity in fibrotic tissues from 72 HCC patients and in normal liver tissues from 59 control subjects was determined along with the severity of hepatofibrosis in hepatocarcinogenesis patients. Similarly, using a rat diethylnitrosamine-induced hepatocarcinogenesis model, CYP2E1 activity at the hepatofibrosis and hepatocarcinogenesis stages was determined, the correlation between CYP2E1 activity at the hepatofibrosis stage and hepatocarcinogenesis was explored, and the impact of inhibition of CYP2E1 activity on hepatocarcinogenesis was studied. The results showed that while CYP2E1 activity in HCC patients with underlying hepatofibrosis was increased, the severity of hepatofibrosis did not correlate with CYP2E1 activity. In the rat hepatocarcinogenesis model, unexpectedly, CYP2E1 activity was found to decrease from hepatofibrosis to hepatocarcinogenesis. Importantly, however, hepatofibrotic rats with higher CYP2E1 activity developed a more severe form of HCC. Moreover, inhibition of CYP2E1 activity could decrease the occurrence and development of HCC in rats. In conclusion, higher CYP2E1 activity may be a risk factor for hepatocarcinogenesis from hepatofibrosis, which raises the possibility of screening patients with hepatofibrosis for CYP2E1 activity to better estimate their risk for hepatocarcinogenesis.

From the Editor’s desk....: September 2018

From the Editor’s desk....: September 2018

Cytotoxic Effect of Fusarium Equiseti Fungus Metabolites Against N-Nitrosodiethylamine- and CCL4-Induced Hepatocarcinogenesis in Rats

Fusarium equiseti, an endophytic fungus isolated from the marine alga Padina pavonica, displayed in vitro potent cytotoxicity and selectivity against liver cancer (HEP-G2) cells. This endophyte was therefore submitted to large-scale liquid fermentation to isolate 11 bioactive constituents. The cytotoxic effect of the extract against in vivo hepatocellular carcinoma (HCC) was evaluated in rats with HCC induced by single intraperitoneal injection of N-nitrosodiethylamine (NDEA) followed by subcutaneous injections of CCl4. After the injection of carcinogen, the fungal extract was orally administered in 25, 50 and 100 mg/kg doses once a day for 10 weeks. The high levels of liver injury and liver cancer markers after NDEA administration were significantly decreased by this treatment with the total fungal metabolites. Histological observations of the liver tissues of rats treated with NDEA and fungal extract co-administered at 100 mg/kg are correlated with the biochemical observations. These findings confirm that F. equiseti total metabolites could restore the activity of hepatic marker enzymes of NDEA-induced hepatocarcinogenesis in rats.

Genetic inactivation of Nrf2 prevents clonal expansion of initiated cells in a nutritional model of rat hepatocarcinogenesis

Dysregulation of the Keap1-Nrf2 pathway has been observed in experimental and human tumors, suggesting possible roles of the pathway in cancer development. Herein, we examined whether Nrf2 (Nfe2l2) activation occurs at early steps of rat hepatocarcinogenesis, to assess critical contributions of Nrf2 to the onset of hepatocellular carcinoma (HCC). We used wild-type (WT) and Nrf2 knockout (Nrf2KO) rats treated with a single injection of diethylnitrosamine (DENA) followed by choline-devoid methionine-deficient (CMD) diet. This experimental model causes massive fatty liver and steatohepatitis with fibrosis and enables identification of early stages of hepatocarcinogenesis. We found that Nrf2 activation takes place in early preneoplastic lesions identified by the marker glutathione S-transferase placental form (GSTP). Nrf2 missense mutations, known to disrupt the Keap1-Nrf2 binding, were present in 65.7% of GSTP-positive foci. Nrf2KO rats were used to directly investigate whether Nrf2 is critical for initiation and/or clonal expansion of DENA-damaged hepatocytes. While Nrf2 genetic inactivation did not alter DENA-induced initiation, it led to increased liver injury and chronic compensatory hepatocyte regeneration when rats were fed a CMD diet. However, in spite of such a permissive environment, the livers of Nrf2KO rats did not display any preneoplastic lesion unlike those of WT rats. These results demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease: i) Nrf2 is activated at early steps of the tumorigenic process and ii) Nrf2 is mandatory for the clonal expansion of initiated cells, indicating that Nrf2 is critical in the onset of HCC. Dysregulation of the Keap1-Nrf2 molecular pathway has been observed in human tumors. In a nutritional model of hepatocarcinogenesis, the protein Nrf2 is frequently mutated/activated at early steps of the tumorigenic process. Herein, we show that Nrf2 is mandatory for the development of preneoplastic lesions. These results suggest that Nrf2 has a critical role in the onset of hepatocellular carcinoma.

HINOKITIOL-AMELIORATED DIETHYLNITROSAMINE-INDUCED HEPATOCARCINOGENESIS THROUGH ANTIOXIDANT MECHANISM IN RATS: IN VITRO AND IN VIVO STUDY

Objective: Chemoprevention seems to be the best strategy for lowering the incidence of liver cancer. Therefore, this study has been initiated to investigate the hinokitiol (HIOL) supplementation which could prevent oxidative stress induced by hepatocarcinogen, diethylnitrosamine (DEN) in rats.Methods: The biochemical parameters such as tissue damaging enzymes, namely, alanine transaminase (ALT), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and attack-free period and enzymatic antioxidants, namely, glutathione (GSH), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), superoxide dismutase (SOD), and histopathological changes were estimated.Results: DEN-treated rats shows increased ALT, ALP, and AST and decreased GSH, GST, CAT, GPx, GR, and SOD activities in liver tissues. The DEN-treated group (200 mg/kg body weight single intraperitoneal injection) with phenobarbital 0.05% orally showed the severe histopathological lesions in liver tissue. Whereas, the groups received HIOL along with DEN shown a comparatively lesser damage. Here, the HIOL supplementation ameliorated the biochemical parameters as well as evoked enzymatic antioxidants in DEN-induced rats to the control values.Conclusion: The HIOL possesses potent antioxidant property, in this credence to that conception, the treatment with HIOL may prevent the development of chemical-induced hepatocarcinogenesis in rats by free radical scavenging mechanism.

Spironolactone in Combination with α-glycosyl Isoquercitrin Prevents Steatosis-related Early Hepatocarcinogenesis in Rats through the Observed NADPH Oxidase Modulation.

Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.

Apigenin loaded nanoparticle delayed development of hepatocellular carcinoma in rats

Hepatocellular carcinoma (HCC) is one of the major causes of cancer related death globally. Apigenin, a dietary flavonoid, possesses anti-tumor activity against HCC cells in-vitro. Development, physicochemical characterization of apigenin loaded nanoparticles (ApNp), biodistribution pattern and pharmacokinetic parameters of apigenin upon intravenous administration of ApNp, and effect of ApNp treatment in rats with HCC were investigated. Apigenin loaded nanoparticles had a sustained drug release pattern and successfully reached the hepatic cancer cells in-vitro as well as in liver of carcinogenic animals. ApNp predominantly delayed the progress of HCC in chemical induced hepatocarcinogenesis in rats. Quantification of apigenin by liquid chromatography–mass spectroscopy (LC-MS/MS) showed that apigenin availability significantly increased in blood and liver upon ApNp treatment. Apigenin loaded nanoparticle delivery substantially controlled the severity of hepatocellular carcinoma and could be a future hope for lingering the survival in hepatic cancer patients.

Augmentation of diethylnitrosamine–induced early stages of rat hepatocarcinogenesis by 1,2-dimethylhydrazine

Diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH) are classical carcinogens used in experimental rodent carcinogenesis. However, the interaction effects of these carcinogens on biochemical and molecular changes during carcinogenesis have not been investigated. Therefore, the effect of DEN and DMH co-administration on preneoplastic lesion formation and its molecular mechanism in rats were determined. Triple intraperitoneal administrations of DEN were made before, during or after double subcutaneous injections of DMH. At week 8 of the experiment, the preneoplastic hepatic glutathione-S-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci (ACF) were analyzed. The combined treatment of these carcinogens increased toxicity to rats. Administration of DMH alone did not induce hepatic GST-P positive foci, while co-treatment with DMH enhanced hepatic GST-P positive foci formation. However, DEN did not influence the size or number of colonic ACF. The treatment with DMH alone induced CYP2E1 and P450 reductase, demonstrating that DMH enhanced DEN metabolism in DEN- and DMH-treated rats. These findings were related to increases in hepatic O6-methylguanine DNA adducts and hepatotoxicity, which are associated with the induction of cell proliferation and liver cancer development. DEN-induced early stages of rat hepatocarcinogenesis were synergistically promoted by DMH via metabolic enzyme induction leading to enhanced DNA mutation and hepatocarcinogenicity.

Vitamin D3 suppresses the early stages of chemically induced hepatocarcinogenesis in rats: a dose-response analysis

BackgroundThe aim of this study was to investigate dose-response effects of vitamin D3 (VD3) supplementation on the early stages of diethylnitrosamine (DEN) and carbon tetrachloride (CCl4)-induced hepatocarcinogenesis in rats.MethodsThe animals were randomly allocated into six experimental groups (10 rats each) treated as follows: group 1: no treatment; groups 2–6: single intraperitoneal injection of N-diethylnitrosamine; groups 2–6: intragastric CCl4; groups 3–6: intragastric VD3 at 10,000, 20,000, 40,000, and 60,000 IU/kg b.w., respectively.ResultsSerum 25-hydroxyvitamin D (25-OHD) levels in the VD3-supplemented groups were significantly higher than those in the control groups (G1 and G2, p < 0.001). Serum levels of phosphate were higher in the groups supplemented with VD3 at 10,000 and 60,000 IU/kg (G3 and G6, p < 0.005). VD3 higher doses reduced cell proliferation and the number of larger placental glutathione S-transferase (GST-P)-positive hepatocellular preneoplastic lesions. Neither the DEN/CCl4 regimen nor the VD3 supplementation altered vitamin D receptor (VDR) protein expression in the liver.ConclusionThe results indicate that high-dose VD3 supplementation reduced the development of DEN/CCl4-induced preneoplastic lesions in the liver.

Therapeutic role of calcium and vitamin K3 in chemically induced hepatocarcinogenesis – new tools for cancer treatment

HCC has been reported to be immensely occurring carcinoma worldwide. Recent days the mortality occurred due to liver cancer has also been found to be increased at an alarming speed affecting mostly the young patients. The aim of the current study was to decipher the role of calcium and vitamin K3 in the treatment of chemically induced hepatocarcinogenesis in the male Wistar rats. Liver cancer was induced via a subnecrogenic dose of 160 mg/kg body weight, diethylnitrosamine (DENA) when associated with fasting/refeeding in male Wistar rats. It elevated the serum glutamate oxaloacetate (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), bilirubin, total cholesterol (CH), triglycerides (TG), alfa-fetoprotein (AFP) and reduced high-density lipoprotein (HDL). Histopathological examination of liver tissue showed marked carcinogenicity of the chemical carcinogen. Food, water intake and animal weights were also assessed, respectively. The animals exposed to DENA showed a significant decrease in the body weight. The elevated levels of serum SGOT, SGPT, ALP, AFP, TC and TG were restored by administration of calcium and Vit K (ad libitum) combination at higher dose than the normal dietary requirement (3 mg/kg) daily for 12 weeks p.o. Physiological and biochemical analysis showed the beneficial effects of calcium and vitamin K3 combination in the animals exposed to DENA. The results deciphered the beneficial effects of calcium and vitamin K3 in combination.

Genetic inactivation of Nrf2 prevents clonal expansion of carcinogen-initiated cells in a nutritional model of rat hepatocarcinogenesis

Genetic inactivation of Nrf2 prevents clonal expansion of carcinogen-initiated cells in a nutritional model of rat hepatocarcinogenesis

SAT-124 - Nrf2 pathway plays an important role in the development of hepatocellular carcinoma: the gene expression signature of Nrf2 observed in a rat hepatocarcinogenesis model

SAT-124 - Nrf2 pathway plays an important role in the development of hepatocellular carcinoma: the gene expression signature of Nrf2 observed in a rat hepatocarcinogenesis model

Effect of diosmin on apoptotic signaling molecules in N-nitrosodiethylamine-induced hepatocellular carcinoma in experimental rats.

The aim of the present study was to evaluate the antioxidant and chemopreventive efficiency of diosmin against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in adult male rats. Rats were classified into four groups as follows: Group I: Control, Group II: NDEA-induced hepatocellular carcinogenic rats, Group III: Cancer-bearing animals treated with diosmin (200mg/kg/body weight/day) orally for 28 days, Group IV: Control animals treated with diosmin (200mg/kg/body weight/day) alone for 28 days. The model of NDEA-induced HCC rats elicited significant increases in alpha-fetoprotein (AFP), lipid peroxidation (LPO) and increase in anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1) with a concomitant significant decline in liver antioxidant enzymes, pro-apoptotic (Bax and Bad) and caspase-3 &-9 proteins. The oral administration of diosmin as a protective agent normalized the altered levels of AFP, LPO, antioxidant enzymes, pro- and anti-apoptotic proteins as well as caspase-3 and -9 proteins. Transmission electron microscopical studies also revealed that treatment of diosmin has a perspective anti-cancer activity by rearranging hepatic cell structure and its integrity. Results of this study suggest that diosmin may be one of a pharmacological and therapeutic representative against hepatocellular carcinoma.

Evaluation of the Liver Cancer Prevention of Anthocyanin Extracts from Mulberry (&amp;lt;i&amp;gt;Morus alba&amp;lt;/i&amp;gt; L.) Variety PR-01

This study aims to evaluate the preventive effects of anthocyanins extracts (MAEs) from mulberry variety PR-01 against N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis in rats. It was found that 150 mg·kg-1 MAEs treatment significantly reduced the NDEA-induced hepatic nodules incidence and hepatocellular carcinoma incidence by 58.30% and 41.70% compared to the model group. Meanwhile, MAEs significantly restored the elevated the liver function enzymes, inhibited the tumor necrosis factor alpha and interleukin-6 levels, elevated the serum interleukin-10 and interferon-γ and increased hepatic glutathione-S-transferase and UDP-glucuronosyltransferase 2B1 enzyme activity. Moreover, 150 mg·kg-1 MAEs supplement enhanced glutathione content and the activities of superoxide dismutase, catalase, glutathione peroxidase activities but reduced the malondialdehyde and thiobarbituric acid-reactive substances content by 37.90% and 44.52%. Furthermore, MAEs pretreatment maintained nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1, heme oxygenase-1, and NAD(P)H: quinine oxidoreductase1 stimulation and inhibited the expression of TNF-α, nuclear factor-kappaB (NF-κB), and cyclooxygenase-2 (COX-2), indicating that MAEs exhibit effectively prevention effects against liver cancer via decreased lipid peroxidation, induced Nrf2-mediated antioxidant enzymes and attenuating the inflammatory mediators COX-2 through NF-κB pathway. Thus, MAEs of mulberry variety PR-01 may be used as a good functional dietary supplement against liver cancer.

Regulation of PKB/Akt-pathway in the chemopreventive effect of lactoferrin against diethylnitrosamine-induced hepatocarcinogenesis in rats

Regulation of PKB/Akt-pathway in the chemopreventive effect of lactoferrin against diethylnitrosamine-induced hepatocarcinogenesis in rats

Ellagic Acid Holds Promise Against Hepatocellular Carcinoma in an Experimental Model: Mechanisms of Action

This research work was initiated to explore the efficacy of ellagic acid in mitigation of hepatocarcinogenesis in rats. Rats were distributed into 4 groups; negative control, hepatocellular carcinoma (HCC), doxorubicin and ellagic acid. Serum alpha-fetoprotein (AFP), glypican-3 (GPC-3), signal transducer and activator of transcription 3 (STAT3) and suppressors of cytokine signaling 3 (SOCS3) levels were assayed by ELISA. Immunohistochemical examination of hepatic VEGF expression was also conducted, along with histological procedures for examination of liver tissue sections. Significant elevation in serum AFP, GPC-3 and STAT3 levels with a significant drop in SOCS3 were observed in the HCC group. In contrast, the treated groups showed significant decline in serum AFP, GPC-3 and STAT3 levels and significant increase in SOCS3. Additionally, the HCC group declared mild positive immunoreaction for VEGF in hepatocytes while treatment with doxorubicin or ellagic acid was associated with a negative immunoreaction for VEGF. These results were supported by histological examination of liver tissue. The obtained findings suggested that ellagic acid may have beneficial chemopreventive role against hepatocarcinogenesis through its apoptotic, antiangiogenic and antiproliferative activities.