Effect of Rapamycin Alone and in Combination with Sorafenib in an Orthotopic Model of Human Hepatocellular Carcinoma

Abstract

Purpose: 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. Experimental Design: 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.Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third cause of cancer-related death globally. There are many methods in the treatment of HCC such as chemotherapy by using new antitumor drugs, operation, intervene therapy, liver transplantation (LT), and so on. Liver resection is still the mainstay of treatment for HCC and provides the consistent long-term survival. However, the resectability is limited by tumor extent, location, or underlying liver dysfunction, with only a minority of HCC being potentially resectable. All these leave LT rather than liver resection as the only potentially curative option, which increase the possibilities of HCC resection for patients with nonresectable tumor or severe hepatic failure. It is reported that the 5-year survival for HCC patients undergoing LT has been steadily improved from 25.3% in 1987 to 61.1% during the most recent period studied (1). Despite the total hepatectomy and liver replace, recurrence and metastasis remained the major obstacles to more prolonged survival after LT for HCC (2). Thereby, novel therapeutic strategies to prevent recurrence after...

Everolimus Augments the Effects of Sorafenib in a Syngeneic Orthotopic Model of Hepatocellular Carcinoma

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