Inhibition of Hepatitis C Virus Replication In Vitro by
                    Xanthohumol, A Natural Product Present in Hops

Sai Lou; Yi-Min Zheng; Shan-Lu Liu; Jianming Qiu; Qunying Han; Na Li; Qianqian Zhu; Pingping Zhang; Cuiling Yang; Zhengwen Liu

doi:10.1055/s-0033-1360172

Planta Medica, Table of Contents

Planta Med 2014; 80(02/03): 171-176
DOI: 10.1055/s-0033-1360172

Biological and Pharmacological Activity

Original Papers

Georg Thieme Verlag KG Stuttgart · New York

Inhibition of Hepatitis C Virus Replication In Vitro by Xanthohumol, A Natural Product Present in Hops

Sai Lou

¹Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xiʼan Jiaotong University, Xi’ an, Shaanxi, China

,

Yi-Min Zheng

²Department of Molecular Microbiology and Immunology, School of Medicine, Bond Life Sciences Center, University of Missouri-Columbia, Columbia, MO, USA

,

Shan-Lu Liu

²Department of Molecular Microbiology and Immunology, School of Medicine, Bond Life Sciences Center, University of Missouri-Columbia, Columbia, MO, USA

,

Jianming Qiu

³Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS, USA

,

Qunying Han

¹Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xiʼan Jiaotong University, Xi’ an, Shaanxi, China

,

Na Li

¹Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xiʼan Jiaotong University, Xi’ an, Shaanxi, China

,

Qianqian Zhu

¹Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xiʼan Jiaotong University, Xi’ an, Shaanxi, China

,

Pingping Zhang

¹Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xiʼan Jiaotong University, Xi’ an, Shaanxi, China

,

Cuiling Yang

¹Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xiʼan Jiaotong University, Xi’ an, Shaanxi, China

,

Zhengwen Liu

¹Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xiʼan Jiaotong University, Xi’ an, Shaanxi, China

› Author Affiliations

Abstract

Hepatitis C virus is a major cause of chronic liver disease worldwide. Xanthohumol, a prenylated flavonoid from hops, has various biological activities including an antiviral effect. It was previously characterized as a compound that inhibits bovine viral diarrhea virus, a surrogate model of hepatitis C virus. In the present work, xanthohumol was examined for its ability to inhibit hepatitis C virus replication in a cell culture system carrying replicating hepatitis C virus RNA replicon. 0.2 % DMSO and 500 units/mL interferon-alpha treatments were set as a negative and positive control, respectively. The inhibitory effect by xanthohumol was determined by the luciferase activity of the infected Huh7.5 cell lysates and the hepatitis C virus RNA levels in the culture. Xanthohumol at 3.53 µM significantly decreased the luciferase activity compared to the negative control (p < 0.01). Xanthohumol at 7.05 µM further decreased the luciferase activity compared to xanthohumol at 3.53 µM (p = 0.015). Xanthohumol at 7.05 µM or 14.11 µM achieved an inhibitory effect similar to that of interferon-alpha 2b (p > 0.05). Xanthohumol at 3.53 µM significantly reduced the hepatitis C virus RNA level compared to the negative control (p = 0.001). Although the results of xanthohumol at 7.05 µM had a higher variation, xanthohumol at the 7.05 µM and 14.11 µM decreased the hepatitis C virus RNA level to that achieved by interferon-alpha (p > 0.05). In conclusion, xanthohumol displays anti-hepatitis C virus activity in a cell culture system and may be potentially used as an alternative or complementary treatment against the hepatitis C virus.

Key words

hepatitis C virus - xanthohumol - Humulus lupulus - Cannabaceae - HCV cell culture

Full Text

References

References
1 Lavanchy D. The global burden of hepatitis C. Liver Int 2009; 29 (Suppl. 01) 74-81
2 Ghany MG, Strader DB, Thomas DL, Seeff LB. American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335-1374
3 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales jr. FL, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982
4 McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS. IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580-593
5 Ferenci P, Laferl H, Scherzer TM, Maieron A, Hofer H, Stauber R, Gschwantler M, Brunner H, Wenisch C, Bischof M, Strasser M, Datz C, Vogel W, Löschenberger K, Steindl-Munda P. Austrian Hepatitis Study Group. Peginterferon alfa-2a/ribavirin for 48 or 72 weeks in hepatitis C genotypes 1 and 4 patients with slow virologic response. Gastroenterology 2010; 138: 503-512 512.e1
6 Lee SS, Roberts SK, Berak H, Dusheiko GM, Harley HA, Gane EJ, Husa P, Horsmans YJ, Hadziyannis SJ, Jenny Heathcote E, Messinger D, Tatsch F, Han KH, Ferenci P. Safety of peginterferon alfa-2a plus ribavirin in a large multinational cohort of chronic hepatitis C patients. Liver Int 2012; 32: 1270-1277
7 Poordad F, McCone jr. J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP. SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195-1206
8 Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S. ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: 2405-2416
9 Halfon P, Locarnini S. Hepatitis C virus resistance to protease inhibitors. J Hepatol 2011; 55: 192-206
10 Stevens JF, Taylor AW, Deinzer ML. Quantitative analysis of xanthohumol and related prenylflavonoids in hops and beer by liquid chromatography-tandem mass spectrometry. J Chromatogr A 1999; 832: 97-107
11 Gerhauser C, Alt A, Heiss E, Gamal-Eldeen A, Klimo K, Knauft J, Neumann I, Scherf HR, Frank N, Bartsch H, Becker H. Cancer chemopreventive activity of Xanthohumol, a natural product derived from hop. Mol Cancer Ther 2002; 1: 959-969
12 Stevens JF, Page JE. Xanthohumol and related prenylflavonoids from hops and beer: to your good health!. Phytochemistry 2004; 65: 1317-1330
13 Kuete V, Ngameni B, Wiench B, Krusche B, Horwedel C, Ngadjui BT, Efferth T. Cytotoxicity and mode of action of four naturally occuring flavonoids from the genus Dorstenia: gancaonin Q, 4-hydroxylonchocarpin, 6-prenylapigenin, and 6,8-diprenyleriodictyol. Planta Med 2011; 77: 1984-1989
14 Zanoli P, Zavatti M. Pharmacognostic and pharmacological profile of Humulus lupulus L. J Ethnopharmacol 2008; 116: 383-396
15 Cho YC, Kim HJ, Kim YJ, Lee KY, Choi HJ, Lee IS, Kang BY. Differential anti-inflammatory pathway by xanthohumol in IFN-gamma and LPS-activated macrophages. Int Immunopharmacol 2008; 8: 567-573
16 Peluso MR, Miranda CL, Hobbs DJ, Proteau RR, Stevens JF. Xanthohumol and related prenylated flavonoids inhibit inflammatory cytokine production in LPS-activated THP-1 monocytes: structure-activity relationships and in silico binding to myeloid differentiation protein-2 (MD-2). Planta Med 2010; 76: 1536-1543
17 Stevens JF, Miranda CL, Frei B, Buhler DR. Inhibition of peroxynitrite-mediated LDL oxidation by prenylated flavonoids: the alpha, beta-unsaturated keto functionality of 2′-hydroxychalcones as a novel antioxidant pharmacophore. Chem Res Toxicol 2003; 16: 1277-1286
18 Miranda CL, Stevens JF, Ivanov V, McCall M, Frei B, Deinzer ML, Buhler DR. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro . J Agric Food Chem 2000; 48: 3876-3884
19 Tabata N, Ito M, Tomoda H, Omura S. Xanthohumols, diacylglycerol acyltransferase inhibitors, from Humulus lupulus . Phytochemistry 1997; 46: 683-687
20 Casaschi A, Maiyoh GK, Rubio BK, Li RW, Adeli K, Theriault AG. The chalcone xanthohumol inhibits triglyceride and apolipoprotein B secretion in HepG2 cells. J Nutr 2004; 134: 1340-1346
21 Buckwold VE, Wilson RJ, Nalca A, Beer BB, Voss TG, Turpin JA, Buckheit 3rd RW, Wei J, Wenzel-Mathers M, Walton EM, Smith RJ, Pallansch M, Ward P, Wells J, Chuvala L, Sloane S, Paulman R, Russell J, Hartman T, Ptak R. Antiviral activity of hop constituents against a series of DNA and RNA viruses. Antiviral Res 2004; 61: 57-62
22 Cos P, Maes L, Vlietinck A, Pieters L. Plant-derived leading compounds for chemotherapy of human immunodeficiency virus (HIV) infection – an update (1998–2007). Planta Med 2008; 74: 1323-1337
23 Zhang N, Liu Z, Han Q, Chen J, Lou S, Qiu J, Zhang G. Inhibition of bovine viral diarrhea virus in vitro by xanthohumol: comparisons with ribavirin and interferon-alpha and implications for the development of anti-hepatitis C virus agents. Eur J Pharm Sci 2009; 38: 332-340
24 Zhang N, Liu Z, Han Q, Chen J, Lv Y. Xanthohumol enhances antiviral effect of interferon alpha-2b against bovine viral diarrhea virus, a surrogate of hepatitis C virus. Phytomedicine 2010; 17: 310-316
25 Yang M, Li N, Li F, Zhu Q, Liu X, Han Q, Wang Y, Chen Y, Zeng X, Lv Y, Zhang P, Yang C, Liu Z. Xanthohumol, a main prenylated chalcone from hops, reduces liver damage and modulates oxidative reaction and apoptosis in hepatitis C virus infected Tupaia belangeri . Int Immunopharmacol 2013; 16: 466-474
26 Herker E, Harris C, Hernandez C, Carpentier A, Kaehlcke K, Rosenberg AR, Farese jr. RV, Ott M. Efficient hepatitis C virus particle formation requires diacylglycerol acyltransferase-1. Nat Med 2010; 16: 1295-1298
27 Nahmias Y, Goldwasser J, Casali M, van Poll D, Wakita T, Chung RT, Yarmush ML. Apolipoprotein B-dependent hepatitis C virus secretion is inhibited by the grapefruit flavonoid naringenin. Hepatology 2008; 47: 1437-1445
28 De Clercq E. The race for interferon-free HCV therapies: a snapshot by the spring of 2012. Rev Med Virol 2012; 22: 392-411
29 Chatel-Chaix L, Germain MA, Götte M, Lamarre D. Direct-acting and host-targeting HCV inhibitors: current and future directions. Curr Opin Virol 2012; 2: 588-598
30 Dorn C, Kraus B, Motyl M, Weiss TS, Gehrig M, Schölmerich J, Heilmann J, Hellerbrand C. Xanthohumol, a chalcone derived from hops, inhibits hepatic inflammation and fibrosis. Mol Nutr Food Res 2010; 54 (Suppl. 02) S205-S213
31 Dorn C, Heilmann J, Hellerbrand C. Protective effect of xanthohumol on toxin-induced liver inflammation and fibrosis. Int J Clin Exp Pathol 2012; 5: 29-36
32 Nozawa H. Xanthohumol, the chalcone from beer hops (Humulus lupulus L.), is the ligand for farnesoid X receptor and ameliorates lipid and glucose metabolism in KK-A(y) mice. Biochem Biophys Res Commun 2005; 336: 754-761
33 Thomopoulos KC, Theocharis GJ, Tsamantas AC, Siagris D, Dimitropoulou D, Gogos CA, Labropoulou-Karatza C. Liver steatosis is an independent risk factor for treatment failure in patients with chronic hepatitis C. Eur J Gastroenterol Hepatol 2005; 17: 149-153
34 Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592-599
35 Dorn C, Bataille F, Gaebele E, Heilmann J, Hellerbrand C. Xanthohumol feeding does not impair organ function and homoeostasis in mice. Food Chem Toxicol 2010; 48: 1890-1897
36 Hussong R, Frank N, Knauft J, Ittrich C, Owen R, Becker H, Gerhäuser C. A safety study of oral xanthohumol administration and its influence on fertility in Sprague Dawley rats. Mol Nutr Food Res 2005; 49: 861-867
37 Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice C. Complete replication of hepatitis C virus in cell culture. Science 2005; 309: 623-626
38 Lou S, Xu B, Huang Q, Zhi N, Cheng F, Wong S, Brown K, Delwart E, Liu Z, Qiu J. Molecular characterization of the newly identified human parvovirus 4 in the family Parvoviridae. Virology 2012; 422: 59-69
39 Guan W, Wong S, Zhi N, Qiu J. The genome of human parvovirus b19 can replicate in nonpermissive cells with the help of adenovirus genes and produces infectious virus. J Virol 2009; 83: 9541-9553