title: Niclosamide enhances ROS-mediated cell death through c-Jun activation.
abstract: Radiotherapy is an effective treatment modality in the clinical treatment of cancers, and has been combined with chemotherapy in order to improve therapeutic efficacy. Therefore, we aimed to develop small molecules that enhance the cytotoxic effects of radiotherapy. In this study, we provide evidence that niclosamide is an effective radiosensitizer in non-small cell lung cancer cells. Using a cell-based high-throughput viability screen of 1040 compounds in combination with γ-ionizing radiation (IR), we found niclosamide, an FDA-approved antihelminthic agent, had a radiosensitizing effect on H1299 human lung cancer cells. Pretreatment with niclosamide enhanced IR- induced cell death of H1299 in a dose-dependent manner via apoptosis compared with IR or niclosamide alone. The combined treatment induced significantly more phosphorylation of p38 MAPK and c-Jun in H1299 cells than IR or niclosamide alone. Since IR induces apoptosis through generation of reactive oxygen species (ROS), hydrogen peroxide (H2O2) was employed as another ROS generator and we found that niclosamide also sensitized cells to H2O2. Niclosamide pretreatment also induced c-Jun and its phosphorylation in the presence of H2O2, thereby enhancing apoptosis. N-acetyl-L-cysteine (NAC) treatment abolished both cell death and c-Jun activation induced by the combination treatments. Knockdown of c-Jun also decreased PARP cleavage and clonogenic cell survival in niclosamide- and IR-treated H1299 cells. Our findings suggest that niclosamide could be a promising radiosensitizer in lung cancer patients through activation of the p38 MAPK-c-Jun axis.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro Nowon-gu, Seoul 139-706, Republic of Korea.
authors.forename: Sae-lo-oom
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro Nowon-gu, Seoul 139-706, Republic of Korea; Department of Chemistry, Hanyang University, 22 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: A-Rang
authors.initials: AR
authors.lastname: Son
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro Nowon-gu, Seoul 139-706, Republic of Korea. Electronic address: ahnjy@kirams.re.kr.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Ahn
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro Nowon-gu, Seoul 139-706, Republic of Korea. Electronic address: immu@kcch.re.kr.
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
mesh_terms: D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D009534:Niclosamide / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D009534:Niclosamide; D006861:Hydrogen Peroxide; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Apoptosis; C-Jun; Drug repositioning; Niclosamide; Radiosensitizer; Radiotherapy; p38 MAPK