Abstract
BackgroundReactivation of hepatitis B virus is a common complication that occurs in patients with hepatitis B virus (HBV) infection who have received cytotoxic chemotherapy or immunosuppressive therapy. This clinical phenomenon not only occurs in overt HBV infection patients but also occurs in patients with resolved HBV infection. Previous research has confirmed that epirubicin and dexamethasone can stimulate HBV replication and expression directly rather than indirectly through immunosuppression. Mitomycin and 5-fluorouracil are currently used as cytotoxic chemotherapy drugs for cancer patients. Leflunomide and mycophenolic acid are regarded as immunosuppressants for autoimmune diseases, and numerous clinical studies have reported that these drugs can reactivate HBV replication. In this study, we aimed to investigate whether mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid induce HBV reactivation directly rather than indirectly through immunosuppression.MethodsTo observe the effect of mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid on HBV replication and expression, we employed HepG2.2.15 and HBV-NLuc-35 cells as a cell model. Next, by native agarose gel electrophoresis (NAGE), quantitative PCR (qPCR), luciferase assay and HBV e antigen (HBeAg) enzyme-linked immunosorbent assay (ELISA) we detected changes in HBV replication and expression induced by these drugs. We also investigated whether lamivudine could inhibit the observed phenotype. SPSS 18.0 software was employed for statistical analysis, One-way ANOVA was used to compare multiple groups.ResultsExpression of HBV capsids and HBeAg in HepG2.2.15 cells was increased by increasing concentration of mitomycin, 5-fluorouracil, leflunomide, and mycophenolic acid. This phenomenon was also demonstrated in HBV-NLuc-35 cells, and the expression of capsids and luciferase activity increased in the same concentration-dependent manner. Replication levels of intracellular capsid DNA and extracellular HBV DNA in HepG2.2.15 cells gradually increased in a dose-dependent manner. In addition, although epirubicin, mitomycin, 5-fluorouracil, dexamethasone, leflunomide and mycophenolic acid enhanced HBV replication, lamivudine inhibited this process.ConclusionOur study confirmed that mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid directly upregulated HBV replication and expression in vitro. This effect was investigated not only in HepG2.2.15 cells but also in the HBV-NLuc-35 replication system. Moreover, this effect could be prevented by nucleoside analogs, such as lamivudine (LAM). Thus, for patients with HBV infection, prophylactic antiviral therapy is necessary before receiving cytotoxic chemotherapy or immunosuppressive therapy.
Highlights
Reactivation of hepatitis B virus is a common complication that occurs in patients with hepatitis B virus (HBV) infection who have received cytotoxic chemotherapy or immunosuppressive therapy
We aimed to investigate whether mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid induce HBV replication in the same manner; we employed HepG2.2.15 cells as a cell model [19]
Cell proliferation toxicity test We used the CCK-8 reagent to detect the cell proliferation toxicity of drugs in HepG2.2.15 cells which treated with different concentrations of epirubicin, mitomycin, 5fluorouracil, dexamethasone, leflunomide, and mycophenolic acid at the indicated times
Summary
Reactivation of hepatitis B virus is a common complication that occurs in patients with hepatitis B virus (HBV) infection who have received cytotoxic chemotherapy or immunosuppressive therapy. Leflunomide and mycophenolic acid are regarded as immunosuppressants for autoimmune diseases, and numerous clinical studies have reported that these drugs can reactivate HBV replication. We aimed to investigate whether mitomycin, 5-fluorouracil, leflunomide and mycophenolic acid induce HBV reactivation directly rather than indirectly through immunosuppression. Reactivation of hepatitis B is a common complication that occurs in patients with HBV infection who receive cytotoxic chemotherapy or immunosuppressive therapy [1,2,3,4]. Numerous clinical studies have reported that mitomycin [1], 5fluorouracil [1, 16], leflunomide [17], and mycophenolic acid [18] treatment can reactivate HBV replication. We investigated the effect of these cytotoxic chemotherapy drugs and immunosuppressants on the new HBV replication system HBV-NLuc-35 cells [20], which are generated by transfecting the pTRE-sNLuc vector into HepG2 TA-7 cells [21, 22] and could stably secrete secNluc recombinant HBV particles, detected the level of secNLuc expression to evaluate HBV replication and expression
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