title: Sorafenib sensitizes human colorectal carcinoma to radiation via suppression of NF-κB expression in vitro and in vivo.
abstract: Over-expression of transcription factor nuclear factor-κB (NF-κB) in the residual tumor after the treatment is often observed at the later period of cancer radiotherapy, results in tumor radioresistance and poor treatment outcome. In this study, we combined sorafenib, a multikinase inhibitor, with ionizing radiation to evaluate the therapeutic effect, and to elucidate the possible mechanism responsible for the radiosensitization of sorafenib on a human HT29/tk-luc colorectal carcinoma in vitro and in vivo. Clonogenic survival and cell cycle analysis were used to evaluate the cytotoxicity of sorafenib in vitro. The combination effect and the role of NF-κB in therapeutic efficacy with respects in apoptosis and tumor cell invasion were studied with HT29/tk-luc tumor-bearing animal model. The expression of NF-κB and its downstream-related proteins were assayed with electrophoretic mobility shift assay (EMSA) and Western blot. Sorafenib combined with radiation shows the synergistic cytotoxicity on HT29/tk-luc cells and increased tumor cell apoptosis. Both EMSA and Western blot show that the NF-κB activity induced by radiation is significantly suppressed by sorafenib. Combination of sorafenib and radiation shows the maximum tumor growth inhibition as compared to that of sorafenib alone or radiation alone in vivo (P<0.001). In conclusion, the effect of sorafenib combined with radiation for the treatment of human colorectal carcinoma is synergistic. The mechanism of synergism is through the inhibition of radiation-induced NF-κB expression and its regulated downstream gene products.
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, No. 155, Sec. 2, Li-Nong St., Bei-tou, Taipei 112, Taiwan.
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Kuo
authors.forename: Wei-Chan
authors.initials: WC
authors.lastname: Lin
authors.forename: I-Tsang
authors.initials: IT
authors.lastname: Chiang
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Chang
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Chen
authors.forename: Shih-Hao
authors.initials: SH
authors.lastname: Su
authors.forename: Chuan-Lin
authors.initials: CL
authors.lastname: Chen
authors.forename: Jeng-Jong
authors.initials: JJ
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D003131:Combined Modality Therapy; D024202:Electrophoretic Mobility Shift Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000187:drug effects / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D016328:NF-kappa B; D010671:Phenylurea Compounds; D011725:Pyridines; D011838:Radiation-Sensitizing Agents; D009536:Niacinamide; D000077157:Sorafenib