title: Mechanism of enhancement of radiation-induced cytotoxicity by sorafenib in colorectal cancer.
abstract: Sorafenib, an orally available multikinase inhibitor, combined with radiation has shown potential as an anticancer treatment in an in vitro and in vivo colon cancer model. In this study, we investigated the mechanism of enhancement of radiation-induced cytotoxicity by sorafenib in colorectal cancer. The effects of sorafenib on radiation-induced cytotoxicity of DLD-1 and HT-29 were evaluated via clonogenic assay. The impact of sorafenib on radiation-induced cell cycle kinetics and on apoptosis was analyzed using flow cytometry. Cyclin B1 was examined by western blot. As a measure of DNA damage after treatment, γ-H2AX foci and nuclear fragmentation were determined as a function of time after irradiation plus sorafenib combination. Tumor growth delay was used to evaluate the effects of sorafenib on in vivo radiation-induced cytotoxicity. Exposure of each cell line to sorafenib combined with irradiation resulted in an increased radiation-induced cytotoxicity with dose enhancement factors at a surviving fraction of 0.37 ranging from 1.13 to 1.76. Sorafenib strengthened radiation-induced accumulation of tumor cells in the G2-M phase with attenuated expression of cyclin B1, but had no effect on radiation-induced apoptosis. Exposure to sorafenib and radiation resulted in a greater number of remaining γ-H2AX foci and fragmented nuclei than radiation alone. In vivo tumor xenograft study confirmed that administration of sorafenib results in significant tumor growth inhibition when combined with radiation. These results indicate that sorafenib enhances radiation-induced cytotoxicity in colorectal cancer and suggest that the mechanism is associated with delaying repair of radiation-induced DNA damage and down-regulation of cyclin B1.
authors.affiliation: Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University, College of Medicine, Seoul, Korea. ybkim3@yuhs.ac
authors.forename: Yong Bae
authors.initials: YB
authors.lastname: Kim
authors.forename: Hei-Cheul
authors.initials: HC
authors.lastname: Jeung
authors.forename: Inhye
authors.initials: I
authors.lastname: Jeong
authors.forename: Kyunghwa
authors.initials: K
authors.lastname: Lee
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Hyun Cheol
authors.initials: HC
authors.lastname: Chung
authors.forename: Gwi Eon
authors.initials: GE
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods*; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects*; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib