Oncotarget

Research Papers:

Gemcitabine, a broad-spectrum antiviral drug, suppresses enterovirus infections through innate immunity induced by the inhibition of pyrimidine biosynthesis and nucleotide depletion

Kyungjin Lee, Dong-Eun Kim, Kyoung-Soon Jang, Seong-Jun Kim, Sungchan Cho _ and Chonsaeng Kim

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Oncotarget. 2017; 8:115315-115325. https://doi.org/10.18632/oncotarget.23258

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Abstract

Kyungjin Lee1,*, Dong-Eun Kim3,*, Kyoung-Soon Jang5, Seong-Jun Kim1, Sungchan Cho3,4 and Chonsaeng Kim1,2

1Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon, South Korea

2Department of Medicinal and Pharmaceutical Chemistry, Korea University of Science and Technology, Daejeon, South Korea

3Anticancer Agent Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea

4Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon, South Korea

5Biomedical Omics Group, Korea Basic Science Institute, Cheongju, South Korea

*These authors have contributed equally to this work

Correspondence to:

Sungchan Cho, email: sungchan@kribb.re.kr

Chonsaeng Kim, email: chonskim@krict.re.kr

Keywords: enterovirus; gemcitabine; antiviral drug; pyrimidine biosynthesis; interferon-stimulated genes (ISGs)

Received: June 13, 2017    Accepted: December 05, 2017    Published: December 15, 2017

ABSTRACT

Gemcitabine, an anti-cancer chemotherapy drug, has additionally shown the antiviral activity against a broad range of viruses and we also have previously reported its synergistic antiviral activity with ribavirin against enteroviruses. As a cytidine analog, gemcitabine has been reported to have an inhibitory activity on the pyrimidine biosynthesis. In addition, a few inhibitors of the pyrimidine biosynthesis have shown to induce the innate immunity in a yet-to-be-determined manner and inhibit the virus infection. Thus, we also investigated whether the anti-enteroviral activity of gemcitabine is mediated by innate immunity, induction of which is related with the inhibition of the pyrimidine synthesis. In this study, we found that the addition of exogenous cytidine, uridine and uridine mono-phosphate (UMP) effectively reversed the antiviral activity of gemcitabine in enterovirus-infected as well as enteroviral replicon-harboring cells, demonstrating gemcitabine’s targeting of the salvage pathway. Moreover, the expression of several interferon (IFN)-stimulated genes (ISGs) was significantly induced by the treatment of gemcitabine, which was also suppressed by the co-treatment with cytidine. These results suggest that the antiviral activity of gemcitabine involves ISGs induced by the inhibition of the pyrimidine biosynthesis.


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