Inhibition of tumor growth and metastasis by rapamycin alone or in combination with sorafenib in an immunocompetent orthotopic rat HCC model.

<p>Rats with MH tumors were treated with vehicle, rapamycin (2 mg/kg/d), sorafenib (30 mg/kg/d) or combination (both rapamycin and sorafenib) starting on day 10 after tumor implantation. <b>A</b>, The combination therapy showed a significantly stronger suppression of tumor growth rate in comparison with both single agent-treated groups. Tumor growth was monitored each week by ultrasonography from day 17 after tumor implantation. <b>B</b>, <b>C</b>, RT-PCR, Western blot analysis and immunohistochemistry showed that rapamycin significantly up-regulated the expression and phosphorylation of PDGFRβ, as well as the phosphorylation of AKT and ERK. In combination with sorafenib, rapamycin-induced activation of PDGFRβ, AKT and ERK were significantly inhibited as were <i>in vitro</i> results (magnification, ×200). <b>D</b>, Significant tumor necrosis in the combination treatment group was visualized by hematoxylin-eosin staining (magnification, ×40). As shown by PCNA and TUNEL, combination treatment also showed more significant greater effects than rapamycin or sorafenib alone in inhibiting tumor cell proliferation and inducing apoptosis of HCC cells (magnification, ×200). The combination therapy also showed significantly fewer tumor vessels than both single agent-treated groups(magnification, ×200). Data are expressed as mean ± SE; *P<0.05, Student's <i>t</i> test (versus rapamycin treatment group).