stilbenes and Hepatitis-C--Chronic

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Chronic hepatitis C virus (HCV) infection causes induction of several tumors/cancer stem cell (CSC) markers and is known to be a major risk factor for development of HCC. Therefore, drugs that simultaneously target viral replication and CSC properties are needed for a risk-free treatment of advanced stage liver diseases, including HCC. Here, we demonstrated that (Z)-3,5,4'-trimethoxystilbene (Z-TMS) exhibits potent antitumor and anti-HCV activities without exhibiting cytotoxicity to human hepatocytes in vitro or in mice livers. Diethylnitrosamine (DEN)/carbon tetrachloride (CCl4) extensively induced expression of DCLK1 (a CSC marker) in the livers of C57BL/6 mice following hepatic injury. Z-TMS exhibited hepatoprotective effects against DEN/CCl4-induced injury by reducing DCLK1 expression and improving histologic outcomes. The drug caused bundling of DCLK1 with microtubules and blocked cell-cycle progression at G2-M phase in hepatoma cells via downregulation of CDK1, induction of p21(cip1/waf1) expression, and inhibition of Akt (Ser(473)) phosphorylation. Z-TMS also inhibited proliferation of erlotinib-resistant lung adenocarcinoma cells (H1975) bearing the T790M EGFR mutation, most likely by promoting autophagy and nuclear fragmentation. In conclusion, Z-TMS appears to be a unique therapeutic agent targeting HCV and concurrently eliminating cells with neoplastic potential during chronic liver diseases, including HCC. It may also be a valuable drug for targeting drug-resistant carcinomas and cancers of the lungs, pancreas, colon, and intestine, in which DCLK1 is involved in tumorigenesis. Cancer Res; 76(16); 4887-96. ©2016 AACR.

Topics: Animals; Antineoplastic Agents; Antiviral Agents; Blotting, Western; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Flow Cytometry; Hepatitis C, Chronic; Humans; Liver Neoplasms; Mice; Mice, Inbred C57BL; Microtubules; Neoplastic Stem Cells; Stilbenes; Xenograft Model Antitumor Assays

Hepatitis C virus (HCV) core protein plays an important role in the development of hepatic steatosis in patients with chronic HCV infection. Treatment of C57BL/6 mice infected with HCV core recombinant adenoviruses with resveratrol significantly decreased hepatic triacylglycerols (TAG) while the serum TAG level was unaffected. RT-PCR and Western blotting showed that HCV core protein attenuated the expression of Sirt1 and PPAR-α, which would be reversed by resveratrol. This was also confirmed in primary mouse hepatic cells infected with HCV core protein expressing adenovirus. Thus, resveratrol may prevent against hepatic steatosis by blocking the inhibited expression of Sirt1 and PPAR-α induced by HCV core protein.

Topics: Adenoviridae; Animals; Blotting, Western; Cells, Cultured; Fatty Liver; Gastrointestinal Agents; Gene Expression Profiling; Genetic Vectors; Hepacivirus; Hepatitis C, Chronic; Hepatocytes; Liver; Mice; Mice, Inbred C57BL; PPAR alpha; Recombinant Proteins; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Sirtuin 1; Stilbenes; Triglycerides; Viral Core Proteins

To elucidate the effect of antioxidants, resveratrol (RVT) and astaxanthin (AXN), on hepatitis C virus (HCV) replication.. We investigated the effect of recent popular antioxidant supplements on replication of the HCV replicon system OR6. RVT is a strong antioxidant and a kind of polyphenol that inhibits replication of various viruses. AXN is also a strong antioxidant. The replication of HCV RNA was assessed by the luciferase reporter assay. An additive effect of antioxidants on antiviral effects of interferon (IFN) and ribavirin (RBV) was investigated.. This is the first report to investigate the effect of RVT and AXN on HCV replication. In contrast to other reported viruses, RVT significantly enhanced HCV RNA replication. Vitamin E also enhanced HCV RNA replication as reported previously, although AXN did not affect replication. IFN and RBV significantly reduced HCV RNA replication, but these effects were dose-dependently hampered and attenuated by the addition of RVT. AXN did not affect antiviral effects of IFN or RBV.. These results suggested that RVT is not suitable as an antioxidant therapy for chronic hepatitis C.

Topics: Antioxidants; Antiviral Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Hepacivirus; Hepatitis C, Chronic; Humans; Interferons; Resveratrol; Ribavirin; RNA, Viral; Stilbenes; Virus Replication; Xanthophylls