title: Ibulocydine sensitizes human cancers to radiotherapy by induction of mitochondria-mediated apoptosis.
abstract: OBJECTIVE
  Ibulocydine (IB), a novel prodrug of CDK inhibitor, has been reported to have anti-cancer effect in human hepatoma cells. In order to address its feasibility as a radiosensitizer to improve radiotherapeutic efficacy for human cancers, this study was designed.
  
  
  METHODS
  Human cancer cells of lung and colon were treated with IB and/or radiotherapy (RT). The cellular effects were assessed by CCK-8, clonogenic, flow cytometric, and western blotting assays. In vivo radiotherapeutic efficacy was evaluated using the xenograft mouse model.
  
  
  RESULTS
  Combined treatment of IB and RT significantly reduced viability and survival fraction of the cells. Apoptotic cell death accompanied with activation of caspases, decrease in Bcl-2/Bax expression, loss of mitochondrial membrane potential (MMP) leading to release of cytochrome c into cytosol was observed. Recovery of Bcl-2 expression level by introducing Bcl-2 expressing plasmid DNA compromised the loss of MMP and apoptosis induced by IB and RT. In vivo therapeutic efficacy of combined treatment was verified in the xenograft mouse model, in which tumor growth was markedly delayed by RT with IB.
  
  
  CONCLUSIONS
  IB demonstrated the property of sensitizing human cancer cells to RT by induction of mitochondria-mediated apoptosis, suggesting that IB deserves to be applied for chemoradiotherapy.
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seok Soon
authors.initials: SS
authors.lastname: Park
authors.affiliation: Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Young-Jong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Jin
authors.initials: EJ
authors.lastname: Ju
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Seol Hwa
authors.initials: SH
authors.lastname: Shin
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jinhyang
authors.initials: J
authors.lastname: Choi
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jaesook
authors.initials: J
authors.lastname: Park
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Kyoung Jin
authors.initials: KJ
authors.lastname: Lee
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin
authors.initials: J
authors.lastname: Park
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Ji
authors.initials: HJ
authors.lastname: Park
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Ko
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Jin
authors.initials: JJ
authors.lastname: Hwang
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong-Hoon
authors.initials: DH
authors.lastname: Jin
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Suh
authors.affiliation: Graduate School of East-West Medical Science, Kyung Hee University, Yongin, Republic of Korea.
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Cho
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Shin
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Si Yeol
authors.initials: SY
authors.lastname: Song
authors.affiliation: Department of Chemistry, Seoul National University, Republic of Korea. Electronic address: kimbm@snu.ac.kr.
authors.forename: B Moon
authors.initials: BM
authors.lastname: Kim
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: syj@amc.seoul.kr.
authors.forename: Seong-Yun
authors.initials: SY
authors.lastname: Jeong
authors.affiliation: Institute for Innovative Cancer Research, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Development and Commercialization of Anti-cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: ekchoi@amc.seoul.kr.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D045304:Cytochromes c / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C559897:(5-(4-amino-6-bromo-5-carbamoyl-1H-pyrrolo(2,3-d)pyrimidin-1-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl isobutyrate; D019253:Proto-Oncogene Proteins c-bcl-2; D011741:Pyrimidine Nucleosides; D011838:Radiation-Sensitizing Agents; D045304:Cytochromes c; D020169:Caspases
keywords: Apoptosis; Bcl-2; Caspase; Ibulocydine; Mitochondria; Radiotherapy