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.
Department of Oral and Maxillofacial Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
Toyoko
T
Harada
Koji
K
Harada
Yoshiya
Y
Ueyama
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D044182:Benzylisoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D004260:DNA Repair / Q000187:drug effects; D045643:DNA Repair Enzymes / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000628:therapy*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018709:Statistics, Nonparametric; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D052117:Benzodioxoles
D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; D045643:DNA Repair Enzymes; D011838:Radiation-Sensitizing Agents; C006947:cepharanthine; D052117:Benzodioxoles