Mechanism of Synergistic Antitumor Effect of Sorafenib and Interferon-α on Treatment of Renal Cell Carcinoma

The multikinase and tyrosine kinase inhibitor sorafenib has antitumor activity in patients with advanced renal cell carcinoma. Recent reports show the ability of sorafenib to synergize with interferon-α, leading to greater antitumor activity. We examined the underlying mechanism of sorafenib and interferon-α synergism for renal cell carcinoma treatment in vitro and in tumor bearing murine models.We used murine and human renal cell carcinoma cell lines for in vitro cell proliferation assay. ACHN (ATCC®) and RENCA tumors were subcutaneously transplanted into NCr-nu/nu and syngeneic BALB/c mice (Charles River Laboratories, Yokohama, Japan), respectively. Mice were treated with sorafenib and/or interferon-α, and tumor growth was monitored. Immunological assays were done in the RENCA model.In the ACHN and RENCA cell lines combination index analysis clearly revealed the synergistic antiproliferative effects of interferon-α and sorafenib in vitro. In the ACHN NCr-nu/nu model we clearly noted the synergistic antitumor effects of interferon-α and sorafenib, indicating the synergistic direct effects of each drug on tumor growth. In the RENCA BALB/c model flow cytometry showed no change in the proportion of lymphocytes. However, while sorafenib alone did not induce natural killer or cytotoxic T-lymphocyte activity against RENCA in that model, interferon-α alone or combined with sorafenib induced natural killer and cytotoxic T-lymphocyte activity.Our results show the synergistic activity of interferon-α and sorafenib. These findings provided the rationale for combination therapy with interferon-α and sorafenib in patients with advanced renal cell carcinoma.