Sirolimus inhibits growth of human hepatoma cells alone or combined with tacrolimus, while tacrolimus promotes cell growth.
OBJECTIVE
Standard immunosuppression after organ transplantation stimulates tumor growth. Sirolimus has a strong antiproliferative and a tumor inhibiting effect. The purpose is to assess the effect on tumor growth of the immuno-suppressive compounds sirolimus and tacrolimus alone and in combination on cells of human hepatocellular carcinoma.


METHODS
We used the human cell lines SK-Hep 1 and Hep 3B derived from hepatocellular carcinoma. Proliferation analyses after treatment with sirolimus, tacrolimus, or the combination of both were performed. FACS analyses were done to reveal cell cycle changes and apoptotic cell death. The expression of apoptosis-related proteins was estimated by Western blots.


RESULTS
Sirolimus alone or combined with tacrolimus inhibited the growth of both cell lines after 5 d by up to 35% in SK-Hep 1 cells, and by up to 68% in Hep 3B cells at 25 ng/mL. Tacrolimus alone stimulated the growth by 12% after 5 ng/mL and by 25% after 25 ng/mL in Hep 3B cells. We found an increase of apoptotic Hep 3B cells from 6 to 16%, and a G1-arrest in SK-Hep 1 cells with an increase of cells from 61 to 82%, when sirolimus and tacrolimus were combined. Bcl-2 was down-regulated in Hep 3B, but not in SK-Hep 1 cells after combined treatment.


CONCLUSIONS
Sirolimus appears to inhibit the growth of hepatocellular carcinoma cells alone and in combination with tacrolimus. Sirolimus seems to inhibit the growth stimulation of tacrolimus.
Schumacher
Guido
G
Department of General, Visceral, and Transplantation Surgery, Charite Campus Virchow Klinikum, Humboldt University, Augustenburger Platz 1, Berlin 13353, Germany. guido.schumacher@charite.de
Oidtmann
Marijke
M
Rueggeberg
Anne
A
Jacob
Dietmar
D
Jonas
Sven
S
Langrehr
Jan-M
JM
Neuhaus
Ruth
R
Bahra
Marcus
M
Neuhaus
Peter
P
D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology* / Q000503:physiopathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004338:Drug Combinations; D016193:G1 Phase; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology* / Q000503:physiopathology; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology*
D004338:Drug Combinations; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus