title: Paclitaxel pretreatment overcomes hypoxia inducible factor-1α-induced radioresistance acquisition of human hepatoma and lung adenocarcinoma cells.
abstract: OBJECTIVE
  This study delineated the mechanisms of paclitaxel (PTX) assistance in overcoming radioresistance in hepatoma and human lung adenocarcinoma (HLAC) cells.
  
  
  METHODS
  The TUNEL assay was used as an index of radiosensitivity, and the MTT assay assessed the efficacy of various combined PTX/RT treatments. The efficacy of PTX disruptions of hypoxia-inducible factor-1 alpha (HIF-1α) was assessed using Western blotting.
  
  
  RESULTS
  Normoxically overexpressed HIF-1α in hepatoma J5 cells was mechanistically linked to activation of the bFGF/PI3K/Akt pathway because the viability of these cells was strongly inhibited by either Akt inhibitors or an HIF-1α inhibitor. All of the cell lines used were extremely sensitive to PTX, and these effects also correlated excellently with HIF-1α suppression. We designed five combined radiation-PTX protocols of varying dose duration and treatment sequences against CL1-1 cells based on the gathered data. Pretreatment of CL1-1 cells with PTX (100nM) for 24h before irradiation (2.5Gy) was the best combined protocol to achieve maximum radiosensitizing effects.
  
  
  CONCLUSIONS
  Our data clearly indicate that PTX pretreatment is an effective radiosensitizing procedure against HIF-1α-expressing hepatoma and HLAC cells, which are constitutively endowed with radioresistance.
authors.affiliation: Department of Radiation Oncology, Tungs' Taichung Metro Harbor Hospital, Taichung, Taiwan.
authors.forename: Kun-Goung
authors.initials: KG
authors.lastname: Lai
authors.affiliation: Division of Radiotherapy, Cheng Hsin General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chun-Te
authors.initials: CT
authors.lastname: Ho
authors.affiliation: Department of Hemato-Oncology, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan.
authors.forename: Chun-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Cardiovascular Center and Department of Anesthesiology, Taichung Veteran General Hospital, Taichung, Taiwan.
authors.forename: Chu-Ying
authors.initials: CY
authors.lastname: Peng
authors.affiliation: Department of Radiation Oncology, Taipei Medical University and Hospital, Taipei, Taiwan. Electronic address: tzliu@h.tmu.edu.tw.
authors.forename: Tsan-Zon
authors.initials: TZ
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Taipei Medical University and Hospital, Taipei, Taiwan; Department of Radiation Oncology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: solomanc@tmu.edu.tw.
authors.forename: Jeng-Fong
authors.initials: JF
authors.lastname: Chiou
mesh_terms: D000230:Adenocarcinoma; D000077192:Adenocarcinoma of Lung; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D017239:Paclitaxel / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017239:Paclitaxel
keywords: BFGF/PI3K/Akt pathway; HIF-1α; Paclitaxel; Radiosensitization