fumarates and Liver-Neoplasms

Nucleos(t)ide analogues (NAs) suppress hepatitis B virus (HBV) replication, but the risk of hepatocellular carcinoma still remains. The presence of detectable HBV DNA in the serum during NA therapies for chronic hepatitis B patients has been reported to be associated with the risk of hepatocellular carcinoma. In this study, we investigated the antiviral effect of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in chronic hepatitis B patients who had detectable HBV DNA in the serum at least once within a year. Among a total of 77 cases in 7 hospitals that switched NAs from ETV to TAF, 23 patients with detectable HBV DNA in a year before switching were analyzed. When the detection frequencies of HBV DNA in the 1st and 2nd years after switching to TAF were analyzed, they were significantly lower than those in the year before switching (68.8% vs. 34.1% for the 1st year and 21.3% for the 2nd year, P < 0.001 for both). The HBsAg decline tended to be larger after switching than before (-2.5% vs. -3.0% for 1st year and -3.1% for 2nd year), but the difference was not significant. One patient died of a cardiovascular event 11 months after the treatment switch, but no adverse effects due to TAF including renal function were observed. In conclusion, it was suggested that switching from ETV to TAF might be effective to suppress the HBV DNA level further in patients whose HBV DNA is detectable, even if at a very low level.

Topics: Adenine; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Fumarates; Hepatitis B, Chronic; Humans; Liver Neoplasms; Tenofovir; Treatment Outcome

Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality worldwide. Our previous study identified a novel alternative splicing variant of prenyl diphosphate synthase subunit 2 (PDSS2) in HCC characterized by a deletion of exon 2, named PDSS2-Del2, which is devoid of the tumor-suppressive function of full-length PDSS2 (PDSS2-FL). To better understand the clinical significance of PDSS2-Del2, we performed a BaseScope™ assay on an HCC tissue microarray and found that positive staining for PDSS2-Del2 predicted a worse overall survival in patients with HCC (P = 0.02). PDSS2-Del2 levels correlated significantly with microvessel counts in HCC tumor tissues. Importantly, PDSS2-Del2 overexpression functionally promoted HCC metastasis, as demonstrated by in vitro and in vivo migration assays. In vivo assays also demonstrated that PDSS2-Del2 increased angiogenesis in xenografts. Furthermore, we discovered that elevated PDSS2-Del2 expression in HCC tumor cells decreased fumarate levels and activated the canonical nuclear factor-κB pathway. The epithelial-to-mesenchymal transition (EMT) and WNT/β-catenin signaling pathways were also activated by overexpression. Dimethyl fumarate (DMF), a fumaric acid ester, effectively reduced the metastasis induced by PDSS2-Del2 as observed with in vivo spleen-liver metastasis animal experiments. DMF is a prescribed oral therapy for multiple sclerosis and it might be a potential treatment for metastasis of patients with HCC. Early clinical trials are needed to validate its potential in this context.

Topics: Adult; Aged; Alkyl and Aryl Transferases; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Dietary Supplements; Epithelial-Mesenchymal Transition; Female; Fumarates; Humans; Liver Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Microvessels; Middle Aged; Neoplasm Metastasis; Neovascularization, Pathologic; NF-kappa B; Survival Analysis; Wnt Signaling Pathway; Young Adult

Secreting and producing capacities of alpha-fetoprotein (AFP) and albumin (ALB) by human hepatoma cell line (HH2-6) exposed to oxygen free radicals generated by dihydroxyfumarate (DHF) were studied in vitro. It was found that cell number were declined in proportion to DHF concentrations for 48 hrs culture and cell proliferations were inhibited by DHF in growth curve. The amount of AFP secreted per cell (secreting capacity) was decreased at high concentration of DHF (50 micrograms/ml) for 48 hrs culture, and remarkable elevation of AFP-secreting capacity for growth stage was inhibited even by DHF (10 micrograms/ml). On the other hand, ALB-secreting capacity was not affected with DHF. Producing capacities of AFP and ALB were correlated with secreting capacities. Cu, Zn-superoxide dismutase (Cu, Zn-SOD) interfered these reactions. These results suggest that oxygen free radicals inhibit cell proliferations and suppress AFP-secreting and producing capacities of HH2-6 cells selectively.

Topics: Albumins; alpha-Fetoproteins; Carcinoma, Hepatocellular; Cell Division; Free Radicals; Fumarates; Humans; Liver Neoplasms; Oxygen; Tumor Cells, Cultured

Fumaric acid (FA) was examined for its effect on hepatocarcinogenesis in rats fed 3-methyl-4'-(dimethylamino)azobenzene (3-Me-DAB). Male DONRYU rats were given approximately 0.5 g 3-Me-DAB by being fed a diet containing 0.06% 3-Me-DAB for 50 days; they were then given a diet containing 1% FA and drinking water containing 0.025% FA for 51 weeks. The administration of FA effectively suppressed the development of hepatocellular carcinoma, hyperplastic nodules, and hyperplastic areas in the livers of rats fed 3-Me-DAB.

Topics: Animals; Diet; Drug Interactions; Fumarates; Hyperplasia; Liver; Liver Neoplasms; Male; Methyldimethylaminoazobenzene; p-Dimethylaminoazobenzene; Rats

Topics: Alanine Transaminase; Alkaline Phosphatase; Arginine; Aspartate Aminotransferases; Bilirubin; Biopsy; Blood Proteins; Cholesterol; Chronic Disease; Clinical Enzyme Tests; Creatine Kinase; Fumarates; Hepatitis; Hepatitis A; Humans; L-Lactate Dehydrogenase; Liver; Liver Diseases; Liver Neoplasms; Lyases; Methods; Neoplasm Metastasis; Succinates