Abstract

After organ transplantation recurrence of hepatoma occurs in over 50% in patients with high tumor stage. Sirolimus has been shown to inhibit the cell cycle in various cell systems. We examined the effect on growth of the human hepatoma cell lines SK-Hepl and Hep3B using sirolimus, tacrolimus, and a combination of both. FACS Analysis were done to reveal apoptotic cell death. There was a dose dependent growth inhibition of both cancer cell lines after treatment with sirolimus after 5 days ranging from 16% at 1 ng/ml in Hep3B cells to 74% at 100 ng/ml in SK-Hepl and Hep3B cells. Treatment with tacrolimus showed a growth stimulating effect on both tumor cell lines. The combination of sirolimus and tacrolimus at equal doses resulted in growth inhibition of both cell lines. FACS analysis showed an increase of apoptotic Hep3B cells from 6 to 16% when sirolimus and tacrolimus were combined. In SK-Hepl cells, we found a cell cycle arrest in this treatment group from 61 to 82%. No changes were seen in cells treated with tacrolimus alone. Western Blot analysis showed a down-regulation of bcl-2 in Hep3B by 80%, but not in SK-Hepl cells when combined with tacrolimus. We conclude that sirolimus exerts strong inhibition of hepatoma cell growth in contrast to tacrolimus, which stimulates hepatoma cell growth. Sirolimus inhibits the tacrolimus-induced cell proliferation. Immunosuppression including sirolimus may reduce the incidence of tumor recurrence after liver transplantation for hepatoma.