title: Enhancement of radiosensitivity by inhibition of c-Jun N-terminal kinase activity in a Lewis lung carcinoma‑bearing subcutaneous tumor mouse model.
abstract: Stereotactic radiosurgery has been recognized as an effective treatment approach for metastatic brain tumors. By increasing the sensitivity of the tumor to radiation and decreasing the marginal dose, it is possible to improve therapeutic efficacy and decrease side-effects. In radiation-induced cells, c-Jun N-terminal kinase (JNK) signaling mediates the phosphorylation of H2AX, which indicates DNA damage sensitivity and modulates the effect of radiation. Lewis lung cancer (LLC) and breast cancer (4T1) cells were irradiated with a Gamma Knife in cell culture tubes. To evaluate the relationship between radiosensitivity and JNK activity, clonogenic assay was performed. DNA damage response was estimated by γH2AX focus formation assay and apoptosis‑related protein levels were assessed by western blotting. The mice were subcutaneously inoculated with LLC cells, and irradiated concomitantly with JNK inhibitor treatment. The effect of the JNK inhibitor was investigated by tumor volumetry and immunohistochemistry. γH2AX expression, which mediates repair of radiation‑induced DNA damage, was reduced in the cancer cell group pretreated with the JNK inhibitor. This finding shows that JNK inhibition may increase the radiosensitivity in radiated lung and breast cancer cells. For the in vivo study, irradiated tumor growth was significantly delayed in the JNK inhibitor-treated mouse group. Blockade of JNK signaling decreased γH2AX expression and increased apoptosis in the radiation-induced cancer cells. JNK inhibitor may be useful for enhancing the radiosensitivity of lung and breast cancer cells and improving the treatment efficacy of radiosurgical approaches for metastatic brain tumors.
authors: Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, Republic of Korea.
authors: Chun-Hao
authors: CH
authors: Li
authors: Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, Republic of Korea.
authors: Sa-Hoe
authors: SH
authors: Lim
authors: Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, Republic of Korea.
authors: Hyang-Hwa
authors: HH
authors: Ryu
authors: Department of Neurosurgery, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, Republic of Korea.
authors: Kyung-Sub
authors: KS
authors: Moon
authors: Department of Neurosurgery, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, Republic of Korea.
authors: Tae-Young
authors: TY
authors: Jung
authors: Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Medical School and Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do 519-763, Republic of Korea.
authors: Shin
authors: S
authors: Jung
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000628:therapy; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006657:Histones / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011836:Radiation Tolerance; D015398:Signal Transduction
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D006657:Histones; D048031:JNK Mitogen-Activated Protein Kinases; C432165:pyrazolanthrone; C475961:gamma-H2AX protein, mouse