Journal
ONCOTARGET
Volume 8, Issue 70, Pages 115315-115325Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.23258
Keywords
enterovirus; gemcitabine; antiviral drug; pyrimidine biosynthesis; interferon-stimulated genes (ISGs)
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Funding
- Korea Heath Industry Development Institute (KHIDI) - ministry of Health Welfare [HI14C2124]
- National Research Foundation of Korea [NRF-2016K1A1A8A01938649, NRF-2015M3A9C7030128, NRF-2016R1C1B2009585]
- National Research Council of Science & Technology (NST) by the Korea government (MSIP) [CRC-16-01-KRICT]
- KRIBB Research Initiative Programs
- National Research Foundation of Korea [2016K1A1A8A01938649] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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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