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Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Lentinan, beta-(1-->3)-D-glucan, an extract from the edible mushroom, Lentinus edodes, has been reported to show direct antitumor effects and various immunomodulatory effects. S-1 is an oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence, combined treatment of cancer cells with Lentinan and S-1 might exert dramatic antitumor effects on OSCC cells. In this study, the response of human OSCC cells to Lentinan alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (6.9 mg/kg/day, 7 times/week) was administered orally and Lentinan (0.1 mg/kg/day, 2 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The gene expression level of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) was determined using microdissection and RT-PCR, and their protein levels were determined using ELISA. Combined therapy of Lentinan and S-1 markedly exerted antitumor effects on human OSCC xenografts and significantly induced apoptotic cells in tumors treated with Lentinan plus S-1. Microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy. These findings demonstrate that the combination of Lentinan and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.

Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, which is widely used for the treatment of many acute and chronic diseases, and can exert antitumor effects on several human cancer cell lines. However, little is known about the detailed mechanisms of the antitumor activity of Cepharanthine. In the present study, we determined whether Cepharanthine could suppress angiogenesis and growth of human oral squamous cell carcinoma (OSCC) cells in vitro and in vivo. Cepharanthine significantly inhibited expression of two major pro-angiogenic molecules, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), in cultured cells and in cells implanted into the subcutaneous tissue of nude mice. Also, Cepharanthine inhibited the nuclear factor-kappaB (NF-kappaB) activity in human OSCC cells in vitro and in vivo. The decreased expression of VEGF and IL-8 correlated with decreased tumor cell growth and decreased vascularization in vitro and in vivo. These findings suggest that Cepharanthine can suppress angiogenesis and growth of OSCC cells by inhibiting expression of VEGF and IL-8 involved in the blockade of NF-kappaB activity.