Effect of rapamycin alone and in combination with sorafenib in an orthotopic model of human hepatocellular carcinoma.
OBJECTIVE
Novel therapeutic strategies are needed to prevent the tumor recurrence or metastasis after liver transplantation for hepatocellular carcinoma (HCC). This study was to investigate the effect of rapamycin, alone and in combination with sorafenib, on HCC in vivo.


METHODS
Xenograft of a highly metastatic human HCC tumor (LCI-D20) was used to evaluate primary tumor growth and lung metastasis after treatment with rapamycin alone or in combination with sorafenib. Tumor cell proliferation was determined by Ki-67 immunostaining. To detect tumor cell apoptosis, the terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assay was used. Tumor angiogenesis was investigated by using a monoclonal anti-CD31 antibody. A vascular endothelial growth factor ELISA kit was used to measure vascular endothelial growth factor protein levels in the mice serum.


RESULTS
Rapamycin, alone and in combination with sorafenib, strongly inhibited primary tumor growth and lung metastases in LCI-D20 model. Furthermore, the combination therapy significantly enhanced the effect of antitumor on primary tumor growth compared with single treatment with either rapamycin (P < 0.001) or sorafenib (P < 0.001). Rapamycin alone inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Nevertheless, the combination therapy showed a significant inhibition of tumor cell proliferation (P < 0.05). Additionally, the combination therapy also further enhanced suppression of tumor cell angiogenesis compared with rapamycin treatment (P < 0.01). However, the induction of apoptosis in combination therapy group was not significantly higher than in the rapamycin-treated group (P > 0.05).


CONCLUSIONS
The combination therapy of rapamycin and sorafenib could be a new and promising therapeutic approach to the treatment of HCC and prevention of HCC recurrence after liver transplantation.
Wang
Zheng
Z
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai, PR China.
Zhou
Jian
J
Fan
Jia
J
Qiu
Shuang-Jian
SJ
Yu
Yao
Y
Huang
Xiao-Wu
XW
Tang
Zhao-You
ZY
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000008:administration & dosage*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011725:Pyridines / Q000008:administration & dosage*; D020123:Sirolimus / Q000008:administration & dosage*; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D020123:Sirolimus