The enhancement of tumor radioresponse by combined treatment with cepharanthine is accompanied by the inhibition of DNA damage repair and the induction of apoptosis in oral squamous cell carcinoma

In the present study, we investigated whether treatment with cepharanthine, a biscoclaurine alkaloid extracted from Stephania cepharantha improves the response to radiotherapy in the oral squamous cell carcinoma (OSCC) cell lines, HSC2, HSC3 and HSC4. We examined the potential mechanisms that may contribute to the enhanced radiation response induced by cepharanthine. Growth inhibition was observed in vitro with radiation or cepharanthine. A co-operative anti-proliferative effect was obtained when cancer cells were treated with cepharanthine followed by radiation. Cepharanthine also promoted the mitotic death of 3 cell lines by radiation. The results from DNA damage repair analysis in the cultured OSCC cells demonstrated that cepharanthine had a strong inhibitory effect on DNA double-strand break (DSB) repair after radiation. The combined treatment of cepharanthine and radiation led to an increase in the sub-G1 peak as shown by flow cytometry, and markedly induced apoptosis through the activation of caspase-3. Tumor xenograft studies demonstrated that the combination of cepharanthine and radiation caused growth inhibition and tumor regression of OSCC tumors in athymic mice; tumor volume was reduced from 765.7 to 226.3 mm3 in HSC2 cells (p<0.01), 391.6 to 43.7 mm3 in HSC3 (p<0.01), and from 572.6 to 174.2 mm3 in HSC4 cells (p<0.01). In addition, combined therapy markedly increased tumor cell apoptosis. Overall, we conclude that cepharanthine enhances tumor radioresponse by multiple mechanisms that may involve the induction of apoptosis and the inhibition of DNA DSB repair after exposure to radiation.