Effect of low-dose rapamycin on tumor growth in two human hepatocellular cancer cell lines.
OBJECTIVE
Liver transplantation is the best treatment for patients with early hepatocellular carcinoma (HCC) and cirrhosis. A limiting factor for long-term survival remains posttransplant tumor recurrence. Thus, there is widespread discussion about the role of various immunosuppressive agents. The newly developed immunosuppressive drug rapamycin may aid to lower recurrence rates. We investigated the efficiency of rapamycin as compared with previous immunosuppressants in a tumor cell model.


METHODS
We studied two HCC cell lines for cell-cycle and proliferation analyses after treatment with rapamycin or other immunosuppressants. To elucidate the underlying molecular signaling pathway, we performed Western blotting for phosphorylated p70 S6 kinase protein expression.


RESULTS
Low-dose rapamycin inhibited tumor cell growth at doses of 1, 5, and 10 ng/mL, while standard immunosuppressants stimulated growth. A rapamycin dose of 20 ng/mL showed a marked decrease in the growth inhibition of both HCC cell lines compared to low-dose administration.


CONCLUSIONS
Rapamycin in low doses inhibited the growth of two HCC cell lines in vitro. Inhibition of tumor cell growth was observed with a high dose of rapamycin (20 ng/mL), which appears to be the dividing line between growth and inhibition. We postulated that at higher doses the immunosuppressive effect of rapamycin is overrode by its antitumor effects.
Heuer
M
M
Department of General, Visceral and Transplantation Surgery, University Hospital of Essen, Essen, Germany.
Benkö
T
T
Cicinnati
V R
VR
Kaiser
G M
GM
Sotiropoulos
G C
GC
Baba
H A
HA
Treckmann
J W
JW
Broelsch
C E
CE
Paul
A
A
D000704:Analysis of Variance; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus