beta-carotene and Carcinoma--Hepatocellular

Since the incidence of liver cancer is increasing in the world, it is valuable to develop an effective method for its prevention. Various phytochemicals have been shown to suppress liver carcinogenesis in experimental studies. Using these phytochemicals, a clinical trial was conducted. Combination of carotenoids and myo-inositol was found to prevent hepatocellular carcinoma development in patients with chronic viral hepatitis and cirrhosis.

Topics: alpha-Tocopherol; Animals; Anticarcinogenic Agents; beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Cryptoxanthins; Dietary Supplements; Hepatitis, Viral, Human; Humans; Inositol; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Neoplasms; Lycopene; Male; Mice; Mice, Inbred C3H; Tumor Burden; Xanthophylls

Vitamin A and its precursor (β-carotene) have been linked with cancer incidence and mortality. However, the relationship between vitamin A and the prognosis of hepatocellular-carcinoma (HCC) is still unknown. Therefore, we investigated whether dietary intakes of vitamin A, retinol, and β-carotene were associated with survival in patients with HCC who participated in the Guangdong Liver Cancer Cohort (GLCC) study. Patients aged 18-80 years with a diagnosis of incident Primary Liver Cancer (PLC) were enrolled within one month of diagnosis prior to cancer treatment at the Sun Yat-sen University Cancer Center. Dietary information one year before diagnosis of HCC was obtained using a 79-item, validated semiquantitative food frequency questionnaire (FFQ). We restricted the present analysis to 877 HCC patients enrolled in the GLCC between September, 2013 and April, 2017 who had completed FFQ. Cox proportional hazard regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for overall and HCC-specific survival. After a median follow-up of 797 days, 384 deaths were documented, 343 of which died from HCC. The multivariable-adjusted HRs (95% CI) of overall and HCC-specific survival for the highest versus the lowest quartile were 0.70 (0.53-0.94) and 0.68 (0.50-0.92) for vitamin A, and 0.72 (0.54-0.96) and 0.69 (0.51-0.94) for β-carotene, respectively. However, no significant association of dietary retinol intakes with survival outcomes was observed. Our observations suggest that higher prediagnostic dietary intakes of vitamin A and β-carotene were associated with improved overall and HCC-specific survival.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta Carotene; Carcinoma, Hepatocellular; China; Diet; Female; Humans; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Risk Factors; Surveys and Questionnaires; Survival Analysis; Vitamin A; Young Adult

Approximately 2.7 million Americans are chronically infected with hepatitis C virus (HCV). HCV patients with cirrhosis form the largest group of persons at high risk for hepatocellular carcinoma (HCC). Increased oxidative stress is regarded as a major mechanism of HCV-related liver disease progression. Deficiencies in retinoid and carotenoid antioxidants may represent a major modifiable risk factor for disease progression. This study aims to identify key predictors of serum antioxidant levels in patients with HCV, to examine the relationship between retinoid/carotenoid concentrations in serum and hepatic tissue, to quantify the association between systemic measures of oxidative stress and antioxidant status, and to examine the relationship between retinoids and stellate cell activation.. Patients undergoing liver biopsy (n = 69) provided fasting blood, fresh tissue, urine and completed a diet history questionnaire. Serum and questionnaire data from healthy volunteers (n = 11), normal liver tissue from public repositories and patients without liver disease (n = 11) were also collected. Urinary isoprostanes, serum and tissue retinoid concentrations were obtained by UHPLC-MS-MS. Immunohistochemistry for αSMA was performed on FFPE sections and subsequently quantified via digital image analysis. Associations between urinary isoprostanes, αSMA levels, and retinoids were assessed using Spearman correlation coefficients and non-parametric tests were utilized to test differences among disease severity groups.. There was a significant inverse association between serum retinol, lycopene, and RBP4 concentrations with fibrosis stage. Serum β-carotene and lycopene were strongly associated with their respective tissue concentrations. There was a weak downward trend of tissue retinyl palmitate with increasing fibrosis stage. Tissue retinyl palmitate was inversely and significantly correlated with hepatic αSMA expression, a marker for hepatic stellate cell activation (r = -0.31, P < 0.02). Urinary isoprostanes levels were inversely correlated with serum retinol, β-carotene, and RBP4.. A decrease in serum retinol, β-carotene, and RBP4 is associated with early stage HCV. Retinoid and carotenoid levels decline as disease progresses, and our data suggest that this decline occurs early in the disease process, even before fibrosis is apparent. Measures of oxidative stress are associated with fibrosis stage and concurrent antioxidant depletion. Vitamin A loss is accompanied by stellate cell activation in hepatic tissue.

Topics: Actins; Adult; beta Carotene; Biomarkers; Biopsy; Carcinoma, Hepatocellular; Carotenoids; Chromatography, High Pressure Liquid; Cross-Sectional Studies; Disease Progression; Diterpenes; Enzyme-Linked Immunosorbent Assay; Female; Hepatic Stellate Cells; Hepatitis C, Chronic; Humans; Immunohistochemistry; Isoprostanes; Lipid Peroxidation; Liver; Liver Cirrhosis; Liver Neoplasms; Lycopene; Male; Middle Aged; Oxidative Stress; Retinoids; Retinol-Binding Proteins, Plasma; Retinyl Esters; Risk; Severity of Illness Index; Tandem Mass Spectrometry; Vitamin A

Several studies have demonstrated that single carotenoid, including lycopene, β-carotene, and α-carotene, exhibits antimetastatic effects; however, little is known whether multicarotenoids have similar effects. Herein, we investigated the antimetastatic effect of multicarotenoids at physiological serum levels in Taiwanese (MCT at 1.4 μM) and American (MCA at 1.8 μM) populations using human hepatocarcinoma SK-Hep-1 cells in comparison with single carotenoid, such as lycopene (0.3 or 0.6 μM, respectively), α-carotene (0.1 μM), β-carotene (0.4 μM), lutein (0.4 or 0.5 μM, respectively), and β-cryptoxanthin (0.2 μM). Results reveal that MCA treatment exhibited an additive inhibition on invasion, migration and adhesion at 24 and 48 h of incubation, whereas MCT treatment possessed additive inhibition at 48 h of incubation. The antimetastatic action of MCT and MCA involved additive reduction on activities of matrix metalloproteinase (MMP)-2, -9, and protein expression of Rho and Rac 1 but additive promotion on protein expression of tissue inhibitor of MMP (TIMP)-1 and -2. All of these effects were stronger in MCA than in MCT at 24 and 48 h of incubation. These results demonstrate that multi-carotenoids effectively inhibit metastasis of human hepatocarcinoma SK-Hep-1 cells. More in vivo studies are needed to confirm these findings.

Topics: beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cryptoxanthins; Humans; Lutein; Lycopene; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Metastasis; rac1 GTP-Binding Protein; rho-Associated Kinases; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

Helicobacter have been detected in human bile and hepatobiliary tissue. Despite evidence that Helicobacter species promote gallstone formation and hepatobiliary tumors in laboratory studies, it remains unclear whether Helicobacter species contribute to these cancers in humans. We used a multiplex panel to assess whether seropositivity to 15 Helicobacter pylori proteins was associated with subsequent incidence of hepatobiliary cancers in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. We included 64 biliary cancers, 122 liver cancers, and 224 age-matched controls which occurred over the course of 22 years. Helicobacter pylori seropositivity was defined as those positive to ≥ 4 antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major hepatobiliary cancer risk factors. Among the controls, 88% were seropositive to H. pylori at baseline. Among those who subsequently developed hepatobiliary cancer, the prevalence of seropositivity was higher: 100% for gallbladder cancer, 97% of extrahepatic bile duct cancer, 91% of ampula of Vater cancer, 96% of intrahepatic bile duct cancer, and 94% of hepatocellular carcinoma. Although the OR for gallbladder cancer could not be calculated, the OR for the other sites were 7.01 (95% confidence interval [CI]: 0.79-62.33), 2.21 (0.19-25.52), 10.67 (0.76-150.08), and 1.20 (0.42-3.45), respectively, with an OR of 5.47 (95% CI: 1.17-25.65) observed for the biliary tract cancers combined. ORs above 1 were observed for many of the investigated antigens, although most of these associations were not statistically significant.. Seropositivity to H. pylori proteins was associated with an increased risk of biliary tract cancers in ATBC. Further studies are needed to confirm our findings and to determine how H. pylori might influence the risk of biliary tract cancer.

Topics: alpha-Tocopherol; beta Carotene; Biliary Tract Neoplasms; Carcinoma, Hepatocellular; Case-Control Studies; Helicobacter Infections; Humans; Liver Neoplasms; Male; Middle Aged; Randomized Controlled Trials as Topic; Vitamins

The laver (Porphyra tenera), red seaweed, has been reported to have anticancer activity, but little is known about its molecular mechanisms of action. The objective of this study was to determine the effects of laver extract on cancer cell proliferation, invasion, and metastasis in SK-Hep1 cells using migration and invasion assays. We also investigated the relationship of MMP-2/-9 and TIMP-1/-2 expression at both the protein and gene level in SK-Hep1 human hepatoma carcinoma cells after laver extract treatment. Laver extract inhibited cancer cell growth in a dose-dependent manner. In an invasion assay conducted in Transwell chambers, laver extract showed 19.6 and 27.2% inhibition of cancer cell at 200 and 400 μg/mL, respectively, compared to the control. The mRNA levels of both MMP-2 and MMP-9 were down-regulated by laver extract treatment in a dose-dependent manner. Laver extract, at 400 μg/mL, was inhibited by MMP-2 and MMP-9 expressions by 70.1 and 77.0%, respectively. An inverse relationship in the mRNA contents of MMP-2/-9 and TIMP-1/-2 expressions in SK-Hep1 cells was found by laver extract treatment. Our results demonstrate antimetastatic properties of laver extract in inhibiting the adhesion, invasion, and migration of SK-Hep1 human hepatoma cancer cells.

Topics: Antineoplastic Agents; beta Carotene; Carcinoma, Hepatocellular; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chlorophyll; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Invasiveness; Phenol; Plant Extracts; Porphyra; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2

The radioisotope iodine-131 [(131)I] can damage DNA. One way to prevent this is to increase the amount of antioxidants via dietary consumption. The goal of this study was to evaluate the radioprotective effect of fresh acerola pulp and synthetic beta-carotene in Rattus norvegicus hepatoma cells (HTC) in response to [(131)I] exposure in vitro. Cellular DNA damage was subsequently assessed using a cytokinesis block micronucleus assay. The mutagenic and cytotoxic activities of doses of [(131)I] (0.1, 0.5, 1, 5, and 10 µCi), acerola (0.025, 0.125, and 0.25 g acerola pulp/mL), and beta-carotene (0.2, 1, and 2 µM) were evaluated. Radioprotective tests were performed by simultaneous treatment with acerola (0.25 g/mL) plus [(131)I] (10 µCi) and beta-carotene (0.2 µM) plus [(131)I] (10 µCi). Acerola, beta-carotene, and low concentrations of [(131)I] did not induce micronucleus formation in HTC cells; in contrast, high concentrations of [(131)I] (10 µCi) were mutagenic and induced DNA damage. Moreover, neither acerola nor beta-carotene treatment was cytotoxic. However, acerola reduced the percentage of [(131)I]-induced damage, although beta-carotene did not show a similar effect. Thus, our results suggest that acerola diet supplementation may benefit patients who are exposed to [(131)I] during thyroid diagnostics and therapy.

Topics: Animals; Anthocyanins; Antioxidants; Ascorbic Acid; beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Dietary Supplements; DNA; DNA Damage; Flavonoids; Iodine Radioisotopes; Liver Neoplasms; Malpighiaceae; Mutation; Plant Preparations; Radiation-Protective Agents; Rats; Rats, Wistar; Tumor Cells, Cultured

Oral administration of β-carotene (BC) was found to exert opposite effects on plasma levels of vascular endothelial growth factor (VEGF) in two animal models. One study in nude mice injected via tail vein with hepatocarcinoma SK-Hep-1 cells showed that BC decreases the plasma VEGF level, whereas the other study in nude mice injected subcutaneously with prostate tumor PC-3 cells showed that BC increases the plasma VEGF level. Herein we investigated whether BC (0.5-20 μM) possesses diverse effects on VEGF secretion in SK-Hep-1, PC-3 and melanoma B16F10 cells. We found that incubation of SK-Hep-1 cells with BC (1-20 μM) for 6 h significantly decreased VEGF secretion, whereas BC (1-10 μM) significantly increased the VEGF secretion in PC-3 cells. However, these effects disappeared at 12 h of incubation. Similar effects occurred in VEGF mRNA and protein expression after treatment of SK-Hep-1 and PC-3 cells with BC for 6 h. In contrast, BC (0.5-20 μM) did not affect mRNA and protein expression and secretion of VEGF in B16F10 cells. We also found that the proliferation of SK-Hep-1 and B16F10 cells was significantly inhibited by 20 μM BC at 6 and 12 h of incubation, whereas the proliferation of PC-3 cells was significantly inhibited by 20 μM BC at 12 h of incubation. In summary, the present study demonstrated the tumor-specific effect of BC on VEGF secretion in different cancer cell lines.

Topics: Animals; beta Carotene; Carcinoma, Hepatocellular; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Liver Neoplasms; Male; Mice; Prostatic Neoplasms; RNA, Messenger; Vascular Endothelial Growth Factor A

The aim of the present study was to investigate the anticancer and immunity activity of β-carotene in hepatocellular carcinoma (HCC) rats. Three days after transplantation, forty Wistar rats were randomly divided into four groups, each group consisting of 10 animals. These groups were control group (untreated), low-dose β-carotene-treated group (20 mg/kg), middle-dose group (40 mg/kg) and high-dose (60 mg/kg) group. β-Carotene-treated groups were fed with β-carotene (20, 40, 60 mg/kg b.w.) orally for 30 days. Control group was treated with the same volume of physiological saline. Another ten rats were served as the normal group. Results showed that 30 days of β-carotene treatment could significantly inhibit tumour growth, enhance blood NK, IL-2, TNF-α, WBC, TP, ALB and A/G levels, and decrease blood ALT, AST and ALP activities in HCC rats. Pathological analysis of liver tissue showed that β-carotene treatment may decrease damage of liver tissue in HCC rats. It can be concluded that β-carotene may improve the immunity function and inhibit tumour growth in HCC rats.

Topics: Animals; beta Carotene; Carcinoma, Hepatocellular; Cell Line, Tumor; Immunity; Liver Neoplasms; Mice; Neoplasms, Experimental; Rats; Rats, Wistar

Recent studies have demonstrated that vegetable rich diets have protective effects on the occurrence and prognosis of various cancers. In addition to dietary intakes, ascorbic acid and β-carotene are also taken as supplements. The aim of this study was to assess effects of ascorbic acid, β-carotene and their combinations on human hepatocellular carcinoma cell line HepG2. Ascorbic acid and β-carotene were applied to cells as plasma peak concentrations (70 and 8 μM, respectively) and their half concentrations (35 and 4 μM, respectively) for 24 and 48 h. Genotoxic and cytotoxic effects of ascorbic acid and β-carotene were evaluated by alkali single cell gel electrophoresis (SCGE), acridine orange/ethidium bromide staining patterns of cells (apoptosis and necrosis) and lipid peroxidation (thiobarbituric acid reactive substances, TBARS). Results of the SCGE demonstrated that both ascorbic acid and β-carotene caused DNA damage on HepG2 which were also concordant to increased apoptosis and necrosis of cells. Increased TBARS values also demonstrated increased lipid peroxidation in these cells. Results of the present study demonstrates that when dietary intakes of ascorbic acid and β-carotene and their relevant achievable plasma level concentrations were considered, both ascorbic acid and β-carotene induce genotoxic and cytotoxic damage on HepG2 together with increased oxidative damage in contrast to their protective effect on healthy cells. This may be correlated to oxidative status and balance of ROS in hepatocellular carcinoma cells.

Topics: Acridine Orange; Apoptosis; Ascorbic Acid; beta Carotene; Carcinoma, Hepatocellular; Cell Line, Tumor; Comet Assay; DNA Damage; Ethidium; Genome, Human; Hep G2 Cells; Humans; Lipid Peroxidation; Liver Neoplasms; Necrosis; Staining and Labeling; Thiobarbituric Acid Reactive Substances

The chemical investigation of the twigs of Morus mesozygia resulted in the isolation of three new prenylated 2-arylbenzofurans, named moracin KM, LM, and SC (1-3), nine known 2-arylbenzofurans (4-12), and two known flavonoids (13-14). The structures of the new compounds were established as [2'',3'':6,7]-(6-(S)-hydroxymethyl-6-methylpyrano)-2-(3,5-dihydroxyphenyl)benzofuran-5-ol (1), [2'',3'':6,7]-(4,7-dihydro-6-methyloxepine)-2-(3-hydroxy-5-methoxyphenyl)benzofuran-5-ol (2), and [2'',3'':6,7]-(6,6-dimethylpyrano)-2-(3,5-dihydroxyphenyl)benzofuran (3). One of the new compounds, moracin LM (2), displayed modest antioxidant activity, whereas known compounds 4, 13, and 14 showed significant hepatoprotective and antioxidant activities.

Topics: Animals; Antioxidants; Benzofurans; beta Carotene; Carcinoma, Hepatocellular; Cell Survival; Drug Evaluation, Preclinical; Flavonoids; Lipid Peroxidation; Liver Neoplasms; Magnetic Resonance Spectroscopy; Microsomes, Liver; Molecular Structure; Morus; Plant Extracts; Plants, Medicinal; Protective Agents; Rats; Spectrophotometry, Infrared

Topics: Animals; Antineoplastic Agents; beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Cell Line, Tumor; Humans; Lung; Lycopene; Mice; Mice, Nude; Neoplasms, Experimental

Lycopene has been shown to inhibit tumor metastasis in vitro, but it is unclear whether lycopene is antimetastatic in vivo. Here, nude mice were orally supplemented 2 times per week for 12 wk with a low or high dose of lycopene [1 or 20 mg/kg body weight (BW)] or with beta-carotene (20 mg/kg BW). Two weeks after the beginning of supplementation, mice were injected once with human hepatoma SK-Hep-1 cells via the tail vein. Plasma levels of matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) increased gradually in tumor-injected mice (tumor controls) following tumor injection but were markedly lowered by lycopene or beta-carotene supplementation. Ten weeks after tumor injection, mice were killed and tumor metastasis was found to be confined to the lungs. Compared with the tumor controls, high-lycopene supplementation lowered the mean number of tumors from 14 +/- 8 to 3 +/- 5 (P < 0.05) and decreased tumor cross-sectional areas by 62% (P < 0.05). High-lycopene supplementation also decreased the positive rate of proliferating cellular nuclear antigen (PCNA), the level of VEGF, and protein expressions of PCNA, MMP-9, and VEGF in lung tissues. However, high-lycopene increased the protein expression of nm23-H1 (an antimetastatic gene) by 133% (P < 0.001). For most variables measured, effects of lycopene were dose dependent and the effect of beta-carotene was between those of high-dose and low-dose lycopene. These results show that lycopene supplementation reduces experimental tumor metastasis in vivo and suggest that such an action is associated with attenuation of tumor invasion, proliferation, and angiogenesis.

Topics: Animals; beta Carotene; Body Weight; Carcinoma, Hepatocellular; Carotenoids; Cell Line, Tumor; Diet; Dietary Supplements; Gene Expression Regulation; Humans; Interleukin-12; Lung Neoplasms; Lycopene; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasm Metastasis; Neoplasms, Experimental; NM23 Nucleoside Diphosphate Kinases; Proliferating Cell Nuclear Antigen; Vascular Endothelial Growth Factor A

Although hepatitis C and B viruses and alcohol consumption are the major risk factors for hepatocellular carcinoma (HCC), dietary habits may also be relevant. A hospital-based case-control study was conducted in Italy in 1999-2002, including 185 HCC cases and 412 cancer-free controls. Dietary habits were assessed using a validated food-frequency questionnaire to compute nutrient intakes. Odds ratios (OR) and corresponding confidence intervals (CI) were calculated using the energy-adjusted residual models. Inverse association emerged for linoleic acid (OR=0.35 for highest versus lowest tertile; 95% CI: 0.18-0.69) and, possibly, beta-carotene (OR=0.48; 95% CI: 0.24-0.93). Among minerals, iron intake was associated with increased HCC risk (OR=3.00; 95% CI: 1.25-7.23), but the association was considerably reduced when iron from wine was excluded (OR=1.61; 95% CI: 0.78-3.30). In conclusion, a diet rich in linoleic acid containing foods (e.g. white meats and fish) and beta-carotene was inversely related to HCC risk.

Topics: Adult; Aged; Aged, 80 and over; Alcohol Drinking; beta Carotene; Carcinoma, Hepatocellular; Case-Control Studies; Diet; Diet Surveys; Female; Humans; Italy; Linoleic Acid; Liver Neoplasms; Male; Middle Aged; Risk Factors; Surveys and Questionnaires

Retinol and its derivatives (retinoids), which have antioxidant activity and promote cell differentiation, may protect against the development of hepatocellular carcinoma (HCC) by controlling hepatocellular differentiation and reducing inflammatory responses.. We examined prospectively the relationship between prediagnostic serum concentrations of retinol, alpha-carotene; beta-carotene; beta-cryptoxanthin; lutein; lycopene; zeaxanthin; alpha-, gamma-, and delta-tocopherols; and selenium and the risk of developing HCC among 213 patients with HCC and 1087 matched control subjects from a cohort of 18,244 men in Shanghai, China, who were monitored from 1986 through 2001. Odds ratios (ORs) and 95% confidence intervals (CIs) for men by quartile of serum concentrations of micronutrients were estimated by using logistic regression with adjustment for cigarette smoking status, alcohol intake, self-reported history of physician-diagnosed hepatitis or liver cirrhosis at recruitment, and seropositivity for hepatitis B surface antigen (HBsAg). All statistical tests were two-sided.. Men with high prediagnostic serum retinol levels had a lower risk of HCC than men in the lowest quartile (Q2 versus Q1, OR = 0.37, 95% CI = 0.22 to 0.61; Q3 versus Q1, OR = 0.30, 95% CI = 0.17 to 0.50; and Q4 versus Q1, OR = 0.13, 95% CI = 0.06 to 0.26; Ptrend < .001). A statistically significant interaction was observed between retinol and HBsAg seropositivity on HCC risk; HBsAg-positive men in the lowest tertile of retinol had a greater than 70-fold higher risk (OR = 72.7, 95% CI = 31.6 to 167.4) of HCC than HBsAg-negative men in the highest tertile of retinol (Pinteraction = .018). No independent effect of serum levels of alpha-carotene; beta-carotene; beta-cryptoxanthin; lutein; lycopene; zeaxanthin; alpha-, gamma-, and delta-tocopherols; or selenium on HCC risk were observed.. High prediagnostic serum level of retinol is associated with a decreased risk of HCC in this population.

Topics: beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Case-Control Studies; China; Cryptoxanthins; Humans; Incidence; Liver Neoplasms; Logistic Models; Lutein; Lycopene; Male; Micronutrients; Middle Aged; Odds Ratio; Prospective Studies; Risk Assessment; Risk Factors; Selenium; Tocopherols; Vitamin A; Xanthophylls; Zeaxanthins

The carotenoid lycopene has been associated with decreased risks of several types of cancer, such as prostate cancer and hepatoma. Tumor metastasis is the most important cause of cancer death. Although lycopene was shown to inhibit metastasis, the mechanism underlying this action is not well understood. Here, we tested the possibility that lycopene may inhibit cancer cell metastasis by upregulating the expression of nm23-H1, a metastasis suppressor gene, in SK-Hep-1 cells, a highly invasive hepatoma cell line, and we determined migration and invasion activities and the expression of nm23-H1 protein and mRNA. We showed that lycopene inhibited SK-Hep-1 migration and invasion in a bell-shaped manner, with the highest effect at 5 micromol/L (91 and 63% inhibition for migration and invasion, respectively; P < 0.05). At the same test level (10 micromol/L), lycopene was much more effective than beta-carotene in reducing cell invasion (by approximately 870%). In contrast to the effects on migration and invasion, lycopene enhanced nm23-H1 expression at both the protein and mRNA levels; the effects were also bell shaped, and at 5 micromol/L, lycopene enhanced nm23-H1 protein and mRNA expressions by 220 +/- 33 and 153 +/- 22% (P < 0.01), respectively. These bell-shaped effects of lycopene may be related to autoxidation of lycopene at elevated concentrations (> or =10 micromol/L). Significant correlations existed between nm23-H1 protein expression and migration (r2= 0.78, P < 0.001) and between nm23-H1 protein expression and invasion (r2= 0.84, P < 0.001) in lycopene-treated SK-Hep-1 cells. We conclude that lycopene has significant antimigration and anti-invasion activity, and that this effect is associated with its induction of nm23-H1 expression.

Topics: alpha-Tocopherol; Anticarcinogenic Agents; Antioxidants; beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Cell Line, Tumor; Cell Movement; Drug Combinations; Humans; Liver Neoplasms; Lycopene; Neoplasm Invasiveness; NM23 Nucleoside Diphosphate Kinases; Nucleoside-Diphosphate Kinase; Oxidation-Reduction; RNA, Messenger; Up-Regulation

To assess the degree of oxidative stress, we measured plasma ubiquinone-10 percentage (%CoQ-10) in total amounts of ubiquinone-10 in patients with chronic active hepatitis, liver cirrhosis, and hepatocellular carcinoma, and in age-matched control subjects, %CoQ-10 values were 12.9 +/- 10.3 (n = 28), 10.6 +/- 6.8 (n = 28), 18.9 +/- 11.1 (n = 20), and 6.4 +/- 3.3 (n = 16), respectively, showing a significant increase in oxidative stress in patient groups as compared to control subjects. There were no differences in total amounts of ubiquinone-10 and ubiquinol-10 among the four groups. We next measured %CoQ-10 in plasmas obtained from nine patients treated with percutaneous transluminal coronary angioplasty (PTCA). Plasmas were collected when hospitalized, and at the time (0, 4, 8, 12, 16, and 20 hr, and 1, 2, 3, 4, and 7 days) after the PTCA. %CoQ-10 values before and right after PTCA were 9.9 +/- 2.8 and 11.4 +/- 2.0, respectively, reached a maximum (20-45) at 1 or 2 days later, and decreased to 7.9 +/- 2.7 at 7 days after PTCA, indicating an increase in oxidative stress in patients during coronary reperfusion.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Ascorbic Acid; beta Carotene; Bilirubin; Biomarkers; Carcinoma, Hepatocellular; Carotenoids; Female; Hepatitis; Humans; Liver Cirrhosis; Liver Neoplasms; Lycopene; Male; Middle Aged; Oxidative Stress; Reference Values; Ubiquinone; Uric Acid; Vitamin E

We have applied our method for the simultaneous detection of plasma ubiquinol-10 (reduced form) and ubiquinone-10 (oxidized form) (S. Yamashita and Y. Yamamoto, Anal. Biochem. 250, 66-73, 1997) to plasmas of normal subjects (n = 16) and patients with chronic active hepatitis (n = 28), liver cirrhosis (n = 16), and hepatocellular carcinoma (n = 20) to evaluate the pressure of oxidative stress in these patients. The average ubiquinone-10 percentages (+/- S.D.) in total ubiquinone-10 and ubiquinol-10 in the four groups were 6.4 +/- 3.3, 12.9 +/- 10.3, 10.6 +/- 6.8, and 18.9 +/- 11.1, respectively, indicating a significant increase in ubiquinone-10 percentage in patient groups in comparison to normal subjects. These results and a significant decrease in the plasma ascorbate level in patient groups indicate that oxidative stress is evident after the onset of hepatitis and the subsequent cirrhosis and liver cancer.

Topics: Adult; Aged; Aged, 80 and over; Antioxidants; Ascorbic Acid; beta Carotene; Biomarkers; Carcinoma, Hepatocellular; Carotenoids; Cholesterol; Cholesterol Esters; Female; Hepatitis, Chronic; Humans; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Lycopene; Male; Middle Aged; Oxidative Stress; Ubiquinone; Vitamin E

Highly differentiated human cell lines represent a useful in vitro model for the study of carotenoid uptake, metabolism, and function. Carotenoids are usually introduced into tissue culture media either in organic solvents or as micelles, whereas carotenoids are localized in lipoproteins in vivo. Initially, the stability of beta-carotene and alpha-tocopherol in micelles and human lipoproteins under standard tissue culture conditions was compared. Recovery of beta-carotene and alpha-tocopherol was 27% +/- 2% and 73% +/- 2%, respectively, after overnight incubation of micellar beta-carotene and alpha-tocopherol in serum-free medium without cells. This marked loss of beta-carotene was attenuated by inclusion of alpha-tocopherol in micelles. In contrast, recovery of beta-carotene and alpha-tocopherol was 88%-95% when medium containing the total lipoprotein fraction isolated from beta-carotene supplemented individuals was incubated overnight without cells. Cellular accumulation of beta-carotene and alpha-tocopherol from medium containing total lipoproteins (1 mg/ml) was proportional to their concentrations in the lipoprotein fraction (r = 0.94 for beta-carotene and 0.74 for alpha-tocopherol). Cells exhibited similar capability of acquiring beta-carotene and alpha-tocopherol from medium containing either low- or high-density lipoproteins. These data show that lipoproteins represent a stable vehicle for delivery of beta-carotene and alpha-tocopherol to HepG2 human liver cells.

Topics: Adult; beta Carotene; Carcinoma, Hepatocellular; Culture Media, Serum-Free; Drug Carriers; Humans; Lipoproteins; Liver; Liver Neoplasms; Male; Micelles; Middle Aged; Tumor Cells, Cultured; Vitamin E

The high incidence of hepatocellular carcinoma (HCC) in cirrhosis, where previous studies have indicated a severe reduction in several antioxidant vitamin factors, prompted us to compare plasma liposoluble vitamins with tocopherol content in healthy and neoplastic liver tissue in humans. This, with a view to a more positive preventive dietary approach, given the conflicting results obtained by liposoluble vitamin dietary supplementation in different malignancies. Eleven patients with cirrhosis, 18 patients affected by cirrhosis with HCC, and 10 patients with liver metastases (LM) from digestive tract adenocarcinomas were compared with controls who had undergone perlaparoscopic cholecistectomy. Plasma alpha- and beta-carotene, retinol and tocopherol, together with liver tocopherol, from both nonmalignant portions and malignant nodules of the same organ, were determined by high-performance liquid chromatography following a well-assessed technique. The results confirm a trend towards a reduction in circulating carotenoids and tocopherol in cirrhosis and in patients affected by cirrhosis with HCC. Tocopherol content in liver tissue is significantly decreased in cirrhosis (0.26 + 0.03 micromol/g prot., mean + SEM, P < .001) and in cirrhotic areas of the HCC group (0.31 + 0.02, P < .002), with respect to its content in liver specimens of healthy controls (0.46 + 0.03) and in healthy areas of the same organ in patients with LM (0.41 + 0.03). Tocopherol concentration is further reduced by 50% in malignant liver nodules of HCC, with respect to surrounding cirrhotic tissue, whereas in metastatic liver nodules from digestive neoplasms the tocopherol content is almost twice that of healthy surrounding areas. This unpredictable tocopherol behavior in liver specimens, of secondary as opposed to primary malignancies of the liver, affords further insight into the conflicting effects of liposoluble vitamins employed in the chemopreventive treatment of different malignant diseases, where hepatic tocopherol concentration show opposite trends: halved in primary HCC and doubled in LM of digestive adenocarcinomas, with respect to healthy controls.

Topics: Aged; beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Female; Humans; Lipids; Liver; Liver Neoplasms; Male; Middle Aged; Vitamin A; Vitamin E

Recently, a new potent antioxidant was isolated from Tempeh (a traditional fermented soybean food in Indonesia) and was identified as 3-hydroxyanthranilic acid (HAA). This study deals with the antioxidant mechanism of HAA under biological systems and the cytokilling function of HAA to human malignant cells. HAA eliminated free radicals and inhibited the formation of fatty acid hydroperoxide in vitro, suggesting that HAA would serve as an antioxidant in the initial reaction in lipid oxidation systems. Actually, HAA inhibited the formation of the dominant product of membrane lipids, 12-hydroxyeicosatetraenoic acid (12-HETE) at a high concentration, while HAA accelerated 12-HETE formation at a low concentration in mammalian tissue. HAA oxidized glutathione and inhibited superoxide dismutase in vitro. Furthermore, HAA inhibited cell growth and induced apoptosis to HuH-7, a human hepatoma-derived cell line. As long as HAA is taken as a component of Tempeh, and not in large doses as a chemical, it may possibly act as a prooxidant rather than an antioxidant in vivo.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 3-Hydroxyanthranilic Acid; Animals; Antioxidants; Apoptosis; beta Carotene; Carcinoma, Hepatocellular; Female; Food; Glutathione; Glycine max; Humans; Indonesia; Mice; Mice, Inbred BALB C; Oxidative Stress; Superoxide Dismutase; Tumor Cells, Cultured; Vitamin E

The efficiency of beta-carotene as a modulatory agent against clastogenicity induced by cyclophosphamide (CPA), an indirect-acting mutagen, and mitomycin C (MMC), a direct-acting mutagen, was evaluated in human hepatoma cells (Hep G2) using three different treatment regimes. Six doses of beta-carotene, 0.25, 0.5, 1.0, 2.0, 4.0 and 6.0 microM, were tested as pre-treatment, simultaneous treatment and pre- + simultaneous treatment. Since these cells are able to activate mutagens without any exogenous metabolizing system (S9 mix), some problems related to the use of S9 mix were eliminated. The data obtained show a statistically significant decrease in the frequency of micronuclei (MN) induced by CPA when the cells were treated with beta-carotene, for all treatments, and no effect of this provitamin on the clastogenicity of MMC was found. These results reinforce the anticlastogenicity of beta-carotene showing that its action is independent of the treatment regime used. On the other hand, the fact that beta-carotene had a protective action only on CPA-induced MN suggests an effect on activation of the promutagen and emphasizes the important utility of cell lines capable of metabolizing chemical mutagens, in such basic studies.

Topics: beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Cyclophosphamide; Humans; Micronucleus Tests; Mitomycin; Mutation; Tumor Cells, Cultured

A case-control study was carried out in 59 patients with newly diagnosed hepatocellular carcinoma and 101 control subjects, who were all male hepatitis B carriers. The odds ratios of hepatocellular carcinoma occurring among hepatitis B carriers in the lowest quartile and those highest quartile of dietary and serum status were 5.3 (1.9 to 15.0) and 86.9 (20.0 to 377.2), respectively. The odds ratios for hepatitis B carriers in the lowest quartile and those in the highest quartile of dietary and serum beta-carotene status were 1.7 (0.7 to 4.1) and 5.0 (1.9 to 13.2). Vitamin E status did not differ in case patients and control subjects. Low education level, heavy consumption of alcohol, and smoking status were also associated with increased odds of hepatocellular carcinoma. Serum retinol, positively associated with dietary retinol, demonstrated an independent effect on hepatocellular carcinoma. This effect may reflect changes in the physiologic condition of the patients at the time of entering the hospital.

Topics: Adult; beta Carotene; Carcinoma, Hepatocellular; Carotenoids; Case-Control Studies; Diet; Hepatitis B; Humans; Liver Neoplasms; Male; Middle Aged; Odds Ratio; Risk Factors; Socioeconomic Factors; Vitamin A; Vitamin E