title: Targeting Phosphatidylinositol 4-Kinase IIIα for Radiosensitization: A Potential Model of Drug Repositioning Using an Anti-Hepatitis C Viral Agent.
abstract: To investigate which isotype of phosphatidylinositol 4-kinase (PI4K) may affect radiosensitivity and examine whether anti-hepatitis C viral (HCV) agents, some of which have been shown to inhibit PI4K IIIα activity, could be repositioned as a radiosensitizer in human cancer cells.
  
  
  
  U251, BT474, and HepG2 cell lines and normal human astrocyte were used. Ribonucleic acid interference, clonogenic assays, Western blotting, immunofluorescence, annexin V assay, lysotracker staining, and β-galactosidase assay were performed.
  
  
  
  Of the 4 PI4K isotypes, specific inhibition of IIIα increased radiosensitivity. For pharmacologic inhibition of PI4K IIIα, we screened 9 anti-HCV agents by half-maximal inhibitory concentration assay. Simeprevir was selected, and its inhibition of PI4K IIIα activity was confirmed. Combination of simeprevir treatment and radiation significantly attenuated expression of phospho-phospho-PKC and phospho-Akt and increased radiation-induced cell death in tested cell lines. Pretreatment with simeprevir prolonged γH2AX foci formation and down-regulation of phospho-DNA-PKcs, indicating impairment of nonhomologous end-joining repair. Cells pretreated with simeprevir exhibited mixed modes of cell death, including apoptosis and autophagy.
  
  
  
  These data demonstrate that targeting PI4K IIIα using an anti-HCV agent is a viable approach to enhance the therapeutic efficacy of radiation therapy in various human cancers, such as glioma, breast, and hepatocellular carcinoma.
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Jeanny
authors: J
authors: Kwon
authors: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Dan Hyo
authors: DH
authors: Kim
authors: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Ji Min
authors: JM
authors: Park
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Young Hee
authors: YH
authors: Park
authors: Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
authors: Yeo Hyun
authors: YH
authors: Hwang
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Institute of Radiation Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Hong-Gyun
authors: HG
authors: Wu
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea.
authors: Kyung Hwan
authors: KH
authors: Shin
authors: Department of Radiation Oncology, Graduate School of Medicine, Seoul National University, Seoul, Republic of Korea; Medical Science Research Institute, Seoul National University Bundang Hospital, Seongnam, Republic of Korea; Institute of Radiation Medicine, Seoul National University, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea. Electronic address: inah228@snu.ac.kr.
authors: In Ah
authors: IA
authors: Kim
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors*; D000998:Antiviral Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001253:Astrocytes / Q000187:drug effects / Q000528:radiation effects; D001343:Autophagy; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D001943:Breast Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000187:drug effects*; D015536:Down-Regulation; D058492:Drug Repositioning; D004789:Enzyme Activation; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000532:radiotherapy; D006657:Histones / Q000187:drug effects; D006801:Humans; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000069616:Simeprevir / Q000627:therapeutic use*; D014410:Tumor Stem Cell Assay; D001616:beta-Galactosidase / Q000032:analysis
chemical_list: D000998:Antiviral Agents; C468783:H2AX protein, human; D006657:Histones; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D011838:Radiation-Sensitizing Agents; D000069616:Simeprevir; D019870:1-Phosphatidylinositol 4-Kinase; C000618292:PI4KIIIalpha protein, human; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D001616:beta-Galactosidase