The kinase inhibitor Sorafenib impairs the antiviral effect of interferon α on hepatitis C virus replication

被引:11
|
作者
Himmelsbach, Kiyoshi [1 ]
Hildt, Eberhard [1 ]
机构
[1] Paul Ehrlich Inst, Div Virol, D-63225 Langen, Germany
关键词
Hepatitis C virus; Sorafenib; Signal transduction; Cell biology; Interferon alpha; RAF-1; KINASE; CELLS; INFECTION; CARCINOMA; THERAPY; PROTEIN; NS5A; PKR;
D O I
10.1016/j.ejcb.2012.09.001
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Recently, it was shown that the kinase inhibitor Sorafenib efficiently blocks HCV replication by inhibition of c-Raf. However, a longer treatment with higher doses of Sorafenib might be associated with adverse effects. Therefore, it was analysed whether a decreased dose of Sorafenib can be applied in combination with interferon alpha to obtain additive antiviral, but at the same time decreased adverse effects. However, Sorafenib abolishes the inhibitory effect of interferon alpha on HCV replication and vice versa. In order to reveal the underlying mechanisms, we observed that on the one hand IFN alpha activates c-Raf and thereby counteracts the inhibitory effect of Sorafenib on HCV replication that is based on the Sorafenib-dependent inhibition of c-Raf. On the other hand we found that the IFN alpha-induced PKR-phosphorylation depends on c-Raf. So, Sorafenib as a potent inhibitor of c-Raf prevents the IFN alpha-dependent PMR phosphorylation. Moreover, Sorafenib inhibits c-Raf-independent the phosphorylation of STAT1 resulting in an impaired induction of IFN alpha-dependent genes. Taken together, these data indicate that a combined application of Sorafenib and interferon alpha in order to obtain an antiviral effect is not useful since Sorafenib exerts an inhibitory effect on targets that are crucial for the transduction of interferon alpha-dependent antiviral response. (C) 2012 Elsevier GmbH. All rights reserved.
引用
收藏
页码:12 / 20
页数:9
相关论文
共 50 条
  • [31] Pyruvate dehydrogenase kinase regulates hepatitis C virus replication
    Gwon-Soo Jung
    Jae-Han Jeon
    Yeon-Kyung Choi
    Se Young Jang
    Soo Young Park
    Sung-Woo Kim
    Jun-Kyu Byun
    Mi-Kyung Kim
    Sungwoo Lee
    Eui-Cheol Shin
    In-Kyu Lee
    Yu Na Kang
    Keun-Gyu Park
    Scientific Reports, 6
  • [32] Pyruvate dehydrogenase kinase regulates hepatitis C virus replication
    Jung, Gwon-Soo
    Jeon, Jae-Han
    Choi, Yeon-Kyung
    Jang, Se Young
    Park, Soo Young
    Kim, Sung-Woo
    Byun, Jun-Kyu
    Kim, Mi-Kyung
    Lee, Sungwoo
    Shin, Eui-Cheol
    Lee, In-Kyu
    Kang, Yu Na
    Park, Keun-Gyu
    SCIENTIFIC REPORTS, 2016, 6
  • [33] Inhibition of Hepatitis C Virus Replication by a Specific Inhibitor of Serine-Arginine-Rich Protein Kinase
    Karakama, Yuko
    Sakamoto, Naoya
    Itsui, Yasuhiro
    Nakagawa, Mina
    Tasaka-Fujita, Megumi
    Nishimura-Sakurai, Yuki
    Kakinuma, Sei
    Oooka, Masaya
    Azuma, Seishin
    Tsuchiya, Kiichiro
    Onogi, Hiroshi
    Hagiwara, Masatoshi
    Watanabe, Mamoru
    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2010, 54 (08) : 3179 - 3186
  • [34] Antiviral effect of ribavirin plus interferon in chronic hepatitis C
    Ciccorossi, P
    Ricchiuti, A
    Petruccelli, S
    Costa, F
    Bellini, M
    Arpe, P
    Carrara, PD
    Maggi, F
    Vatteroni, L
    Pistello, M
    Bendinelli, M
    Maltinti, G
    Marchi, S
    HEPATOLOGY, 1998, 28 (04) : 474A - 474A
  • [35] EFFECT OF ANTIVIRAL SUBSTANCES ON HEPATITIS-A VIRUS-REPLICATION INVITRO
    BIZIAGOS, E
    CRANCE, JM
    PASSAGOT, J
    DELOINCE, R
    JOURNAL OF MEDICAL VIROLOGY, 1987, 22 (01) : 57 - 66
  • [36] Regulation of hepatitis C virus replication by interferon regulatory factor 1
    Kanazawa, N
    Kurosaki, M
    Sakamoto, N
    Enomoto, N
    Itsui, Y
    Yamashiro, T
    Tanabe, Y
    Maekawa, S
    Nakagawa, M
    Chen, CH
    Kakinuma, S
    Oshima, S
    Nakamura, T
    Kato, T
    Wakita, T
    Watanabe, M
    JOURNAL OF VIROLOGY, 2004, 78 (18) : 9713 - 9720
  • [37] ANTIVIRAL EFFECT OF RECOMBINANT INTERFERON-ALPHA ON HEPATITIS-A VIRUS-REPLICATION IN HUMAN LIVER-CELLS
    CRANCE, JM
    DELOINCE, R
    LEVEQUE, F
    JOUAN, A
    TREPO, C
    COMPTES RENDUS DE L ACADEMIE DES SCIENCES SERIE III-SCIENCES DE LA VIE-LIFE SCIENCES, 1994, 317 (01): : 94 - 97
  • [38] Antiviral potential of interferon-omega on hepatitis B virus replication in human hepatoma cells
    Hagelstein, J
    Kist, A
    Stremmel, W
    Galle, PR
    ARZNEIMITTEL-FORSCHUNG-DRUG RESEARCH, 1998, 48 (03): : 343 - 347
  • [39] Twenty-four hour kinetics of hepatitis C virus and antiviral effect of alpha-interferon
    Boulestin, A
    Kamar, N
    Sandres-Sauné, K
    Legrand-Abravanel, F
    Alric, L
    Vinel, JP
    Rostaing, L
    Izopet, J
    JOURNAL OF MEDICAL VIROLOGY, 2006, 78 (03) : 365 - 371
  • [40] Interfering with interferon: Re-igniting the debate on calcineurin inhibitor choice and antiviral therapy for hepatitis C virus recurrence
    Watashi, Koichi
    Metselaar, Herold J.
    van der Laan, Luc J. W.
    LIVER TRANSPLANTATION, 2008, 14 (03) : 265 - 267