Aim: Despite its known anticancer benefits, monotherapy with sirolimus is not sufficient to achieve optimal immunosuppression to prevent rejection. However, there is no published prospective study to compare the anticancer effect between various immunosuppressive combinations. Therefore, we analyzed the anticancer effects of various immunosuppressive regimens in order to provide experimental evidence for selecting an optimal immunosuppressive regimen after liver transplantation for hepatocellular carcinoma (HCC).
Methods: The Huh7 cell line was used as a model for HCC in both in vitro and in vivo mouse experiments. The immunosuppressant regimens tested were: tacrolimus, sirolimus, MMF, sirolimus plus tacrolimus, and sirolimus plus MMF. 3-(4 5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assays showed that the sirolimus plus MMF combination appeared to be synergistic in its cell suppressive effects, achieving statistically significant lowest cell viability.
Results: In vitro western blot analysis showed that there were lower levels of expression of phosphorylated mammalian target of rapamycin, p70S6K and p4EBP1, transforming growth factor-β and pSmad3 expression in the cells treated with sirolimus, MMF and sirolimus plus MMF. Finally, in the mouse model of tumorigenesis, the sirolimus plus MMF and sirolimus plus tacrolimus showed the most suppressive effect in terms of tumor volume.
Conclusion: Throughout both the in vitro and in vivo experiments, the sirolimus and MMF combination had the most consistent and greatest antiproliferative effects.
Keywords: hepatocellular carcinoma; immunosuppression; sirolimus; transplantation.
© 2015 The Japan Society of Hepatology.