Abstract
Hepatitis C virus (HCV) is the main causative agent of chronic liver disease, which may develop into liver cirrhosis and hepatocellular carcinoma. By using a recently developed reporter assay system in which genome-length HCV RNA replicates efficiently, we found that hydroxyurea (HU), a DNA synthesis inhibitor, inhibited HCV RNA replication. Moreover, we demonstrated that the anti-HCV activity of the combination of IFN-alpha and HU was higher than that of IFN-alpha alone. These results suggest that HU may be an effective anti-HCV reagent that can be used not only singly but also in combination with IFN-alpha to treat chronic hepatitis C.
References
Adams RL, Lindsay JG (1967) Hydroxyurea reversal of inhibition and use as a cell-synchronizing agent. J Biol Chem 242:1314–1317
Bader T, Fazili J, Madhoun M, Aston C, Hughes D, Rizvi S, Seres K, Hasan M (2008) Fluvastatin inhibits hepatitis C replication in humans. Am J Gastroenterol 103:1383–1389
Belt RJ, Haas CD, Kennedy J, Taylor S (1980) Studies of hydroxyurea administered by continuous infusion: toxicity, pharmacokinetics, and cell synchronization. Cancer 46:455–462
Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362
Foli A, Maiocchi MA, Lisziewicz J, Lori F (2007) A checkpoint in the cell cycle progression as a therapeutic target to inhibit HIV replication. J Infect Dis 196:1409–1415
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Gonçales FLJ, Häussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347:975–982
Garcia M, Yu XF, Griffin DE, Moss WJ (2008) Measles virus inhibits human immunodeficiency virus type 1 reverse transcription and replication by blocking cell-cycle progression of CD4+ T lymphocytes. J Gen Virol 89:984–993
Hasford J, Baccarani M, Hehlmann R, Anseri H, Tura S, Zuffa E (1996) Interferon-alpha and hydroxyurea in early chronic myeloid leukemia: a comparative analysis of the Italian and German chronic myeloid leukemia trials with interferon-alpha. Blood 87:5384–5391
Ikeda M, Abe K, Dansako H, Nakamura T, Naka K, Kato N (2005) Efficient replication of a full-length hepatitis C virus genome, strain O, in cell culture, and development of a luciferase reporter system. Biochem Biophys Res Commun 329:1350–1359
Ikeda M, Abe K, Yamada M, Dansako H, Naka K, Kato N (2006) Different anti-HCV profiles of statins and their potential for combination therapy with interferon. Hepatology 44:117–125
Ikeda M, Kato N (2007) Modulation of host metabolism as a target of new antivirals. Adv Drug Deliv Rev 59:1277–1289
Kuo G, Choo QL, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Tegtmeier GE, Bonino F, Colombo WS, Lee WS, Kuo C, Berger K, Shuster JR, Overby LR, Bradley DW, Houghton M (1989) An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362–364
Lori F, Malykh A, Cara A, Sun D, Weinstein JN, Lisziewicz J, Gallo RC (1994) Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science 266:801–805
Lori F, Jessen H, Lieberman J, Finzi D, Rosenberg E, Tinelli C, Walker B, Siliciano RF, Lisziewicz J (1999) Treatment of human immunodeficiency virus infection with hydroxyurea, didanosine, and a protease inhibitor before seroconversion is associated with normalized immune parameters and limited viral reservoir. J Infect Dis 180:1827–1832
Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, Goodman ZD, Koury K, Ling M, Albrecht JK (2001) Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 358:958–965
Mori K, Abe K, Dansako H, Ariumi Y, Ikeda M, Kato N (2008) New efficient replication system with hepatitis C virus genome derived from a patient with acute hepatitis C. Biochem Biophys Res Commun 371:104–109
Naka K, Ikeda M, Abe K, Dansako H, Kato N (2005) Mizoribine inhibits hepatitis C virus RNA replication: effect of combination with interferon-α. Biochem Biophys Res Commun 330:871–879
Pietschmann T, Lohmann V, Rutter G, Kurpanek K, Bartenschlager R (2001) Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. J Virol 75:1252–1264
Saito I, Miyamura T, Ohbayashi A, Harada H, Katayama T, Kikuchi S, Watanabe Y, Koi S, Onji M, Ohta Y, Choo QL, Houghton M, Kuo G (1990) Hepatitis C virus infection is associated with the development of hepatocellular carcinoma. Proc Natl Acad Sci USA 87:6547–6549
Sergerie Y, Boivin G (2008) Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes. Antiviral Res 77:77–80
Tamura T, Matsuzaki M, Harada H, Ogawa K, Mohri H, Okubo T (1997) Upregulation of interferon-alpha receptor expression in hydroxyurea-treated leukemia cell lines. J Investig Med 45:160–167
Tanabe Y, Sakamoto N, Enomoto N, Kurosaki M, Ueda E, Maekawa S, Yamashiro T, Nakagawa M, Chen CH, Kanazawa N, Kakinuma S, Watanabe M (2004) Synergistic inhibition of intracellular hepatitis C virus replication by combination of ribavirin and interferon-alpha. J Infect Dis 189:1129–1139
The Benelux CML, Group Study (1998) Randomized study on hydroxyurea alone versus hydroxyurea combined with low-dose interferon-alpha 2b for chronic myeloid leukemia. Blood 91:2713–2721
Thomas DL (2000) Hepatitis C epidemiology. Curr Top Microbiol Immunol 242:25–41
Watashi K, Hijikata M, Hosaka M, Yamaji M, Shimotohno K (2003) Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology 38:1282–1288
Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, Shimotohno K (2005) Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell 19:111–122
Acknowledgments
The authors thank Kazue Yoshihara and Yoshiko Kubushiro for their technical assistance. This work was supported by a grant for the 2008 Strategic Research Project (No. W20012) provided by Yokohama City University, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nozaki, A., Morimoto, M., Kondo, M. et al. Hydroxyurea as an inhibitor of hepatitis C virus RNA replication. Arch Virol 155, 601–605 (2010). https://doi.org/10.1007/s00705-010-0624-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00705-010-0624-1