Quality diet indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study.

There is limited research on the effect of dietary quality on hepatocellular carcinoma (HCC) risk in populations with relatively high risk of HCC. Using data from Singapore Chinese Health Study, a prospective cohort study, of 63 257 Chinese aged 45 to 74, we assessed four diet-quality index (DQI) scores: the Alternative Health Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI). We identified 561 incident HCC cases among the cohort participants after a mean of 17.6 years of follow-up. Cox proportional hazard regression model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for HCC in relation to these DQI scores. Unconditional logistic regression method was used to evaluate the associations between DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). High scores of AHEI-2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend < .05). Compared with the lowest quartile, HRs (95% CIs) of HCC for the highest quartile of AHEI-2010, aMED and DASH were 0.69 (0.53-0.89), 0.70 (0.52-0.95) and 0.67 (0.51-0.87), respectively. No significant association between HDI and HCC risk was observed. Among HBsAg-negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED (HRQ4vsQ1 = 0.46, 95% CI: 0.23-0.94, Ptrend = .10). These findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC.

Fabrication of Imatinib Mesylate-Loaded Lactoferrin-Modified PEGylated Liquid Crystalline Nanoparticles for Mitochondrial-Dependent Apoptosis in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of concern as it has substantial morbidity associated with it. Previous reports have ascertained the antiproliferative activity of imatinib mesylate (IMS) against diverse types of carcinomas, but limited bioavailability has also been reported. The present study envisaged optimized IMS-loaded lactoferrin (LF)-modified PEGylated liquid crystalline nanoparticles (IMS-LF-LCNPs) for effective therapy of IMS to HCC via asialoglycoprotein receptor (ASGPR) targeting. Results displayed that IMS-LF-LCNPs presented an optimum particle size of 120.40 ± 2.75 nm, a zeta potential of +12.5 ± 0.23 mV, and 73.94 ± 2.69% release. High-resolution transmission electron microscopy and atomic force microscopy were used to confirm the surface architecture of IMS-LF-LCNPs. The results of cytotoxicity and 4,6-diamidino-2-phenylindole revealed that IMS-LF-LCNPs had the highest growth inhibition and significant apoptotic effects. Pharmacokinetics and biodistribution studies showed that IMS-LF-LCNPs have superior pharmacokinetic performance and targeted delivery compared to IMS-LCNPs and plain IMS, which was attributed to the targeting action of LF that targets the ASGPR in hepatic cells. Next, our in vivo experiment established that the HCC environment existed due to suppression of BAX, cyt c, BAD, e-NOS, and caspase (3 and 9) genes, which thus owed upstream expression of Bcl-xl, iNOS, and Bcl-2 genes. The excellent therapeutic potential of IMS-LF-LCNPs began the significant stimulation of caspase-mediated apoptotic signals accountable for its anti-HCC prospect. 1H nuclear magnetic resonance (serum) metabolomics revealed that IMS-LF-LCNPs are capable of regulating the disturbed levels of metabolites linked to HCC triggered through N-nitrosodiethylamine. Therefore, IMS-LF-LCNPs are a potentially effective formulation against HCC.

Coffee and nonalcoholic fatty liver disease: A review.

Nonalcoholic fatty liver disease (NAFLD) is widely prevalent globally and has no effective treatment. Coffee is one of the most popular beverages in the world and can therefore have a significant impact on public health on account of its health-promoting properties. Evidence from observational, clinical, and animal studies suggests that coffee may play an important role in human health. This article summarizes the effects of coffee on liver health, especially on nonalcoholic fatty liver disease (NAFLD) and its progression: liver fibrosis, cirrhosis and hepatocellular carcinoma. In addition, this article describes the pathogenesis, prevalence, diagnosis, and nutrition guidelines relating to NAFLD. Possible mechanisms responsible for the effects of coffee on the liver are also suggested.

Discovery of novel NF-кB inhibitor based on scaffold hopping: 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidine.

NF-κB is a key signaling pathway molecule linking hepatoma and chronic inflammation. Inhibition of NF-κB activation can alleviate inflammation, and promote hepatoma cell apoptosis. In this study, a series of fluoro-substituted 1,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidines (PPMs, 31-57) were synthesized from 3,5-bis(arylidene)-4-piperidones (BAPs, 4-30) based on scaffold hopping. We successfully discovered the most potent 43 substituted by electron-withdrawing substitutes (3-F and 4-CF3) exhibited less toxicity and higher anti-inflammatory activity. Preliminary mechanistic studies revealed that 43 induced dose-dependent cell apoptosis at cell and protein level, while inhibited NF-κB activation by suppressing LPS-induced phosphorylation levels of p65, IκBα and Akt, and by indirectly suppressing MAPK signaling, and by inhibiting the nuclear translocation of NF-κB induced by TNF-α or LPS. Docking analysis verified simulated 43 could reasonably bind to the active site of Bcl-2, p65 and p38 proteins. This compound, as a novel NF-κB inhibitor, also demonstrated both anti-inflammatory and anti-hepatoma activities, warranting its further development as a potential multifunctional agent for the clinical treatment of liver cancers and inflammatory diseases.

Association between Dietary Tomato Intake and the Risk of Hepatocellular Carcinoma: The Singapore Chinese Health Study.

BACKGROUND: Intake of tomato and/or lycopene has been associated with reduced risk of several cancers, but there is no report on the association with risk of hepatocellular carcinoma (HCC). METHODS: The associations of tomato and lycopene consumption with risk of HCC were examined in the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese ages 45 to 74 years at enrollment. Diet was assessed using a validated semiquantitative food frequency questionnaire. Cox proportional hazard regression models were used to estimate HR and its 95% confidence interval (CI) of HCC with the consumption of tomato and lycopene among all cohort participants, and unconditional logistic regression was used to assess the association by hepatitis B surface antigen (HBsAg) positivity in a nested case-control study. RESULTS: After a mean follow-up of 17.6 years, 561 incident HCC cases were identified. Higher tomato intake was associated with lower risk of HCC after adjustment for potential confounders (P trend < 0.001). Compared with the lowest quartile, HRs (95% CIs) of HCC for the second, third, and fourth quartile of tomato intake were 0.70 (0.56-0.88), 0.73 (0.58-0.92), and 0.63 (0.49-0.81). Among HBsAg-negative individuals, the inverse association remained (P trend = 0.03). There was no association between lycopene intake and HCC risk (P trend = 0.54). CONCLUSIONS: Tomato intake may offer protection against the development of HCC, particularly among individuals without chronic infection with hepatitis B virus. IMPACT: Tomato intake is a low-cost preventative measure against HCC that may help reduce risk due to increasing rates of nonalcoholic fatty liver disease.

Curcumin-loaded nanostructured lipid carrier induced apoptosis in human HepG2 cells through activation of the DR5/caspase-mediated extrinsic apoptosis pathway.

Curcumin is a lipophilic anti-cancer compound extracted from turmeric. Our previous study demonstrated that the curcumin-loaded nanostructured lipid carrier (Cur-NLC) exhibits superior anti-cancer activity in inhibiting proliferation as well as inducing apoptosis of human HepG2 cells compared to native curcumin. This study aims to unveil the mechanisms underlying the pro-apoptotic effect of Cur-NLC on HepG2 cells. Evidence indicates that low expression of death receptors (DRs) on cancer cell membranes leads to attenuated apoptosis signaling. This study showed that Cur-NLC significantly increased total expression of DR5 protein while simultaneously upregulated cell membrane expression of DR5. Cur-NLC significantly increased caspase-8 and caspase-3 activities, accompanied by increased apoptosis. Furthermore, enhanced apoptosis was inhibited in the presence of a pan-caspase inhibitor, Z-VAD-FMK. Therefore, Cur-NLC induced activation of the extrinsic apoptosis pathway via modulating the DR5/caspase-8/-3 mediated apoptosis pathway in HepG2 cells, suggesting that Cur-NLC is a promising therapeutic agent or supplement for the treatment of hepatocellular carcinoma.

Prediagnostic dietary intakes of vitamin A and ß-carotene are associated with hepatocellular-carcinoma survival.

Vitamin A and its precursor (ß-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 ß-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 ß-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 ß-carotene were associated with improved overall and HCC-specific survival.

Nutritional diagnosis of patients with hepatocellular carcinoma: what is the best method? / Diagnóstico nutricional de pacientes con carcinoma hepatocelular: ¿cuál es el mejor método?

Introduction: malnutrition is a frequent finding among cancer patients. Despite its prognostic significance, there are still few studies evaluating the nutritional status of patients with hepatocellular carcinoma (HCC). Objectives: to evaluate the nutritional status of patients with HCC by different methods. Methods: patients with HCC were evaluated in an outpatient clinic at the Hospital Santa Casa de Misericórdia de Porto Alegre. The methods used for the nutritional assessment were body mass index (BMI), tricipital skinfold (TSF), arm circumference (AC), arm muscle circumference (AMC), hand grip strength (HGS), adductor pollicis muscle (APM), patient-generated subjective global assessment (PG-SGA) and phase angle (PA). Results: forty-three patients with HCC were evaluated; all of them were cirrhotic. The mean age was 64.0 ± 5.8 years and the prevalent gender was male (72.1%). APM, PA, PG-SGA and AMC were the most sensitive methods for the diagnosis of malnutrition. There was a negative correlation between TSF and Child-Pugh score (p = 0.004) and a positive correlation between APM and BCLC stage (Barcelona Clinic Liver Cancer Group) (p = 0.006). Conclusions: there was high variation in the diagnosis of malnutrition among the methods studied. APM, AMC, PA and PG-SGA can be indicated as tools of choice in the nutritional assessment of the HCC patient because they were the most sensitive methods in the diagnosis of malnutrition. TSF and APM correlate with disease severity

Introducción: la desnutrición es un hallazgo frecuente entre pacientes oncológicos. A pesar de su significancia pronóstica, todavía son escasos los estudios que evalúan el estado nutricional de pacientes con carcinoma hepatocelular (CHC). Objetivos: evaluar el estado nutricional de pacientes con CHC por diferentes métodos. Métodos: se evaluaron pacientes con CHC en seguimiento ambulatorio en el Hospital Santa Casa de Misericordia de Porto Alegre. Los métodos empleados para la evaluación nutricional fueron índice de masa corporal (IMC), pliegue cutáneo tricipital (PCT), circunferencia del brazo (CB), circunferencia muscular del brazo (CMB), fuerza del apretón de manos (FAM), músculo aductor del pulgar (MAP), evaluación subjetiva global producida por el paciente (ASG-PPP) y ángulo de fase (AF). Resultados: se evaluaron 43 pacientes con CHC, todos cirróticos. El promedio de edad fue de 64,0 ± 5,8 años y el sexo prevalente, el masculino (72,1%). MAP, AF, ASG-PPP y CMB fueron los métodos más sensibles para el diagnóstico de desnutrición. Se observó una correlación negativa entre la PCT y la puntuación Child-Pugh (p = 0,004) y una correlación positiva entre MAP y la estadificación BCLC (p = 0,006). Conclusiones: hubo gran variación en el diagnóstico de desnutrición entre los métodos estudiados. MAP, CMB, AF y ASG-PPP se pueden indicar como herramientas de elección en la evaluación nutricional del paciente con CHC por haber sido los métodos más sensibles en el diagnóstico de desnutrición. PCT y MAP se correlacionan con la gravedad de la enfermedad

Phytochemicals, antioxidant activity and hepatoprotective effect of ginger (Zingiber officinale) on diethylnitrosamine toxicity in rats.

Context: Chronic liver damage has serious medical consequences. Objective: To investigate the hepatoprotective effect of dry Zingiber officinale (ginger) and its essential (volatile) oil against diethylnitrosamine (DEN) toxicity in rats. Materials and methods: Phenols and flavonoids components were characterized in dry ginger using HPLC-UV instrument while ginger essential oil (E.O.) was investigated via GC-MS technique. Antioxidant activity was determined in vitro. In rat model, ginger was administrated for 2 months. Lipid profile, antioxidant biomarkers, liver functions and histopathology were assessed. Results: Chlorogenic acid (63.85 ppm) and hesperidin (156.91 ppm) are among the major phenolic and flavonoid constituents in dry ginger. Curcumene (15.21%) and linalool (13.47%) represent the main E.O. constituents. In rats treated with ginger E.O., a significant elevation in serum HDL (31.14%) was accompanied by a decrease in LDL (55.14%). A significant decrease in serum ALT and ALP was reported (56.85% and 53.84%, respectively). Serum GSH-Px activity has significantly increased 75.06%. Meanwhile, E.O. showed anticancer potential against HepG2 cell line (IC50 = 40 µg/mL). Liver histopathological examinations confirmed the protective effect against abnormalities. Conclusion: Ginger was able to reduce the severity of DEN-cytotoxicity in rats, which suggests a novel antioxidant role originating from this medicinal plant.

Impact of Branched-Chain Amino Acid Granule Therapy in Patients with Hepatocellular Carcinoma Who Have Normal Albumin Levels and Low Branched-Chain Amino Acid to Tyrosine Ratios.

Serum albumin has been reported to be a useful indicator of liver function and branched-chain amino acid (BCAA) therapy is associated with a lower incidence of hepatocellular carcinoma (HCC). We investigated the impact of BCAA granule therapy on overall survival and disease-specific survival in patients with normal albumin levels and low BCAA to tyrosine ratio (BTR)s who had treatment-naïve HCC. Overall survival and disease-specific survival was analyzed in 78 patients with HCC who were treated (n = 27) or not treated (n = 51) with BCAAs. Twenty-six patients died during the follow-up period. There were 19, 5, and 2 patients who died due to HCC, hepatic failure, and non-liver-related disease, respectively. Multivariate analysis for factors associated with overall survival indicated that BCAA therapy was independently associated with good prognosis in patients with HCC (hazard ratio [HR], 0.317; 95% confidence interval [CI], 0.123-0.813; P = 0.017). In addition, multivariate analysis using competing risks methods indicated that BCAA therapy is independently associated with reduction of disease-specific mortality (HR, 0.216; 95% CI, 0.068-0.689; P = 0.001). In conclusion, BCAA therapy improved both overall survival and disease-specific survival in HCC patients with low BTRs despite having normal albumin levels.

Protective effects of coffee consumption following liver transplantation for hepatocellular carcinoma in cirrhosis.

BACKGROUND: Increasing evidence suggests that coffee consumption might protect against hepatocellular carcinoma (HCC) and liver cirrhosis-associated death risk. Caffeine is a natural antagonist to extracellular adenosine and exhibits experimental tumoricidal activity. AIM: To evaluate if coffee consumption has beneficial effects on HCC recurrence after orthotopic liver transplantation (OLT). METHODS: Coffee consumption of patients before and after OLT for HCC was assessed and correlated with HCC recurrence. HepG2 cells were analysed for proliferation and metastasis potential after treatment with adenosine, in the presence or absence of adenosine receptor antagonists. Expression of adenosine receptors was determined, and known adenosine-mediated cancer pathways inclusive of MAPK and NF-kappa B were tested. RESULTS: Ninety patients underwent OLT for HCC. Sixteen (17.8%) patients experienced HCC recurrence after median time of 11.5 months (range 1-40.5). For overall survival postoperative coffee intake emerged as major factor of hazard reduction in a multivariate analysis (HR = 0.2936, 95% CI = 0.12-0.71, P = 0.006). Those with such postoperative coffee intake (≥3 cups per day) had a longer overall survival than those who consumed less or no coffee: M = 11.0 years, SD = 0.52 years vs. M = 7.48 years, SD = 0.76 years = 4.7, P = 0.029). CONCLUSIONS: Coffee consumption is associated with a decreased risk of HCC recurrence and provides for increased survival following OLT. We suggest that these results might be, at least in part, associated with the antagonist activity of caffeine on adenosine-A2AR mediated growth-promoting effects on HCC cells.

Dietary intake of genistein suppresses hepatocellular carcinoma through AMPK-mediated apoptosis and anti-inflammation.

BACKGROUND: Women have a lower risk of hepatocellular carcinoma (HCC) than men, and the decreased possibility of HCC in women is thought to depend on estrogen levels. As a soybean-isoflavone product, genistein has estrogenic activity in various reproductive tissues, because it mimics 17ß-estradiol and binds the estrogen receptor. Though genistein is a known liver cancer suppressor, its effects have not been studies in long-term experiment, where genistein is fed to a female animal model of HCC. METHODS: Mice were treated with diethylnitrosamine (DEN) to induce HCC at 2 weeks of age and fed with supplemental genistein for 5 months, from 40 to 62 weeks of age. RESULTS: The dietary intake of genistein decreased the incidence of HCC and suppressed HCC development. Genistein induced phospho-AMPK in total liver extracts, Hep3B cells, and Raw 264.7 cells, and phospho-AMPK promoted apoptosis in liver and Hep3B cells. Moreover, phospho-AMPK down-regulated pro-inflammatory responses and ameliorated liver damage. A suppressed pro-inflammatory response with increased mitochondrial respiration was concomitantly observed after genistein treatment. CONCLUSIONS: Genistein-mediated AMPK activation increases hepatocyte apoptosis through energy-dependent caspase pathways, suppresses the inflammatory response in resident liver macrophages by increased cellular respiration, and consequently inhibits the initiation and progression of HCC.

Therapeutic Efficacy of Vitamin D in Experimental c-MET-ß-Catenin-Driven Hepatocellular Cancer.

Aberrant activation of ß-catenin signaling is frequently observed in hepatocellular cancer. Although Wnt/ß-catenin signaling can be targeted by vitamin D, therapeutic use of vitamin D for this purpose is not currently established. We evaluated the therapeutic use of vitamin D or its analogs using a synthetic transgenic mouse of hepatocarcinogenesis induced by mutant ß-catenin, and MET overexpression in which 75% of mice develop well-differentiated HCC within 8 weeks in the absence of fibrosis. Vitamin D receptor expression was similar in both tumoral and nontumoral tissue. There was no significant difference in overall survival, or in tumor progression assessed by imaging, biochemical, or tumor cell burden assessments in mice receiving a vitamin D-supplemented diet containing 12.0 IU VD/g (HVD) compared with a standard diet (SD) containing 2.3 IU VD/g. Furthermore, systemic treatment with calcitriol [vitamin D analog 1α,25(OH)2D3] or EB1089 (synthetic vitamin D analog) by intraperitoneal injection for 4 weeks prolonged median survival but did not increase overall survival compared with controls. Although tumor formation was delayed in males compared with that in females, there was no difference in overall survival between males and females. In conclusion, although 1α,25(OH)2D3 is reported to inhibit ß-catenin signaling, as well as proliferation, migration, and differentiation in cancer cells, neither dietary supplementation with vitamin D nor treatment with vitamin D analogs altered the formation or growth of HCC associated with ß-catenin activation. These results conclusively demonstrate the lack of utility of targeting vitamin D for therapy of HCC in this setting.

Octahydrocurcumin, a final hydrogenated metabolite of curcumin, possesses superior anti-tumor activity through induction of cellular apoptosis.

The biological activity of curcumin (CUR), a promising naturally occurring dietary compound for the treatment of hepatocellular carcinoma (HCC), was closely associated with its metabolite. Octahydrocurcumin (OHC) is the final hydrogenated metabolite of CUR and has been reported to have potential biological activities. However, difficulties in access have hampered its biological studies. In the current investigation, we designed an efficient synthesis method to produce OHC, and comparatively explored the anti-cancer effect and potential mechanism of OHC and CUR in an H22 ascites tumor-bearing mice model. The results indicated that OHC had a relatively wide margin of safety, and exhibited superior effects to CUR in suppressing the tumor growth, including ascending weight, abdominal circumference, ascites volume and cancer cell viability. OHC significantly induced H22 cell apoptosis by upregulating the p53 expression and downregulating the MDM2 expression. OHC also remarkably decreased the Bcl-2 and Bcl-xl protein expressions, and increased the Bax and Bad expressions in ascitic cells. Furthermore, THC substantially induced the release of cytochrome C, caspase-3, caspase-9 and the cleavage of PARP to induce H22 cell apoptosis. Taken together, OHC was more effective than CUR in suppressing H22-induced HCC through the activation of the mitochondrial apoptosis pathway. OHC may thus be a promising anti-HCC agent.

Analysis of Colchicine-Induced Effects on Hepatoma and Hepatocyte Cells by Atomic Force Microscopy.

Biomechanical properties of cells are altered by many diseases. Cancer cell metastasis is related to the properties such as the cell stiffness that influences cell proliferation, differentiation and migration. In this paper, we used an atomic force microscope to analyze the colchicine-induced effects on the mechanical properties of hepatocyte (HL-7702 cells) and hepatoma cells (SMCC-7721 cells) in culture at the nanoscale. The cells were exposed to a solution with a normal dose of colchicine for two, four and six hours. Surface topographic images showed that colchicine decreased the stability of the cytoskeleton. After the same six-hour treatment in a solution with a normal dose of colchicine, the biomechanical properties of HL-7702 cells were almost unchanged. However, the stiffness and the adhesion force of the SMCC-7721 cells were clearly increased (more than twofold of the normal values), especially after four hours. The deformability of SMCC-7721 cancer cells was significantly decreased within the six-hour treatment in the solution with a normal dose of colchicine. Analysis of the biomechanical properties of post-treatment hepatoma cells provided a complementary explanation for the mechanism of action of colchicine on cells at the nanoscale. This method is expected to allow the monitoring of potential metastatic cancer cell changes, thus preventing the emergence and the transmission of disease, and improving the diagnosis of cancer.

Phytotherapeutics: The Emerging Role of Intestinal and Hepatocellular Transporters in Drug Interactions with Botanical Supplements.

In herbalism, botanical supplements are commonly believed to be safe remedies, however, botanical supplements and dietary ingredients interact with transport and metabolic processes, affecting drug disposition. Although a large number of studies have described that botanical supplements interfere with drug metabolism, the mode of their interaction with drug transport processes is not well described. Such interactions may result in serious undesired effects and changed drug efficacy, therefore, some studies on interaction between botanical supplement ingredients and drug transporters such as P-gp and OATPs are described here, suggesting that the interaction between botanical supplements and the drug transporters is clinically significant.

Vitamin D and K signaling pathways in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver malignancy, and is now the six most common in between malignancies. Early diagnosis of HCC with prompt treatment increases the opportunity of patients to survive. With the advances in understanding the molecular biology of HCC, new therapeutic strategies to treat HCC have emerged. There is a growing consensus that vitamins are important for the control of various cancers. Biochemical evidence clearly indicates that HCC cells are responsive to the inhibitory effect of vitamin D, vitamin D analogues and vitamin K. In this review, we summarize the mechanisms used by vitamin D and K to influence the development of HCC and the latest development of vitamin analogues for potential HCC therapy.

Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation.

The beneficial health properties of the Mediter-ranean diet are well recognized. The principle source of fat in Mediterranean diet is extra-virgin olive oil (EVOO). Oleocanthal (OC) is a naturally occurring minor phenolic compound isolated from EVOO, which has shown a potent anti-inflammatory activity, by means of its ability to inhibit the cyclooxygenase (COX) enzymes COX-1 and COX-2. A large body of evidence indicates that phenols exhibit anticancer activities. The aim of the present study was to evaluate the potential anticancer effects of OC in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) models. A panel of human HCC (HepG2, Huh7, Hep3B and PLC/PRF/5) and CRC (HT29, SW480) cell lines was used. Cells were treated with OC, and cell viability and apoptosis were evaluated. Compared with classical commercially available COX inhibitors (ibuprofen, indomethacin, nimesulide), OC was more effective in inducing cell growth inhibition in HCC and CRC cells. Moreover, OC inhibited colony formation and induced apoptosis, as confirmed by PARP cleavage, activation of caspases 3/7 and chromatin condensation. OC treatment in a dose dependent-manner induced expression of γH2AX, a marker of DNA damage, increased intracellular ROS production and caused mitochondrial depolarization. Moreover, the effects of OC were suppressed by the ROS scavenger N-acetyl-L-cysteine. Finally, OC was not toxic in primary normal human hepatocytes. In conclusion, OC treatment was found to exert a potent anticancer activity against HCC and CRC cells. Taken together, our findings provide preclinical support of the chemotherapeutic potential of EVOO against cancer.

Protective effects of coffee against oxidative stress induced by the tobacco carcinogen benzo[α]pyrene.

AIMS: Coffee consumption has been epidemiologically associated with a lower risk for liver cirrhosis and cancer. UDP-glucuronosyltransferases (UGT1A) catalyze the detoxification of reactive metabolites thereby acting as indirect antioxidants. Aim of the study was to examine UGT1A regulation in response to Benzo[α]pyrene (BaP) to elucidate the potentially protective effects of coffee on BaP-induced oxidative stress and toxicity. RESULTS: In cell culture (HepG2, KYSE70 cells) and in htgUGT1A-WT mice, UGT1A transcription was activated by BaP, while it was reduced or absent htgUGT1A-SNP (containing 10 commonly occurring UGT1A-SNPs) mice. siRNA-mediated knockdown identified aryl hydrocarbon receptor (AhR) and nuclear factor erythroid2-related factor-2 (Nrf2) as mediators of BaP-induced UGT1A upregulation. Exposure to coffee led to a reduction of BaP-induced production of reactive oxygen species in vitro and in htgUGT1A-WT and -SNP mice. After UGT1A silencing by UGT1A-specific siRNA in cell culture, the coffee-mediated reduction of ROS production was significantly impaired compared to UGT1A expressing cells. CONCLUSION: A common UGT1A haplotype, prevalent in 9% (homozygous) of the White population, significantly impairs the expression of UGT1A enzymes in response to the putative tobacco carcinogen BaP and is likely to represent a significant risk factor for reduced detoxification and increased genotoxicity. Coffee was demonstrated to inhibit BaP-induced production of oxidative stress by UGT1A activation, and is therefore an attractive candidate for chemoprotection in risk groups for HCC or other tumors.