Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response
Daunorubicin, a topoisomerase II poison, suppresses viral production of hepatitis B virus by inducing cGAS-dependent innate immune response
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DOI：
10.1016/j.bbrc.2018.08.195
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发表时间：
2018-10-12
影响因子：
3.1
通讯作者：
Kato, Nobuyuki
中科院分区：
文献类型：
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作者：
Imai, Hirotaka;Dansako, Hiromichi;Kato, Nobuyuki
B型肝炎病毒（HBV）引起肝脏疾病，如慢性肝炎、肝硬化和肝细胞癌。这些疾病与持续的HBV感染密切相关。因此，为了防止肝脏疾病的进展，抑制持续的HBV感染是重要的。柔红霉素（DNR）是拓扑异构酶II（TopII）毒物，是临床上使用的具有广谱抗恶性肿瘤活性的抗癌剂。最近报道DNR通过外源性环GMP-AMP合成酶（cGAS）引起DNA损伤依赖性干扰素（IFN）-β诱导，随后抑制埃博拉病毒复制。在本研究中，我们证明，柔红霉素引起细胞增殖的抑制，但不是细胞死亡，通过DNA损伤反应在永生化的人肝细胞NKNT-3/NTCP细胞。有趣的是，DNR触发了内源性cGAS依赖性先天免疫应答，随后抑制了NKNT-3/NTCP细胞中HBV的病毒产生。Top II毒物可能是抗HBV候选药物。(C)2018爱思唯尔公司All rights reserved.
Hepatitis B virus (HBV) causes hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. These diseases are closely associated with persistent HBV infection. To prevent the progression of hepatic diseases, it is thus important to suppress persistent HBV infection. Daunorubicin (DNR), a topoisomerase II (Top II) poison, is a clinically used anticancer agent with a wide spectrum of activity against malignancies. DNR was recently reported to cause DNA damage-dependent interferon (IFN)-beta induction through exogenous cyclic GMP-AMP synthetase (cGAS) and subsequently to suppress Ebola virus replication. In the present study, we demonstrated that DNR caused the inhibition of cell proliferation, but not cell death, through the DNA damage response in immortalized human hepatocyte NKNT-3/NTCP cells. Interestingly, DNR triggered the endogenous cGAS-dependent innate immune response and subsequently suppressed viral production of HBV in NKNT-3/NTCP cells. Top II poisons may be anti-HBV drug candidates. (C) 2018 Elsevier Inc. All rights reserved.