title: SN-38 overcomes chemoresistance of colorectal cancer cells induced by hypoxia, through HIF1alpha.
abstract: BACKGROUND
  Cancer cells can acquire resistance to therapy under hypoxic condition. We aimed to investigate the mechanisms regulating chemoresistance induced by hypoxia.
  
  
  METHODS
  Human colorectal cancer cells, HT-29 and SW480, were cultured under hypoxic conditions and the sensitivity to 5-fluorouracil (FU), oxaliplatin, and SN-38 (active metabolite of irinotecan) was tested. The cell cycle was evaluated by flow cytometry after staining of cells with propidium iodide (PI). hypoxia-inducible factor 1α (HIF-1α) expression was evaluated by western blot analysis.
  
  
  RESULTS
  Hypoxia induced strong G(0)/G(1) cell cycle arrest of cancer cells and abrogated the cytotoxic effects of 5-FU and oxaliplatin, but not that of SN-38. This effect was dependent on the significant inhibition of the accumulation of HIF-1α in cancer cells cultured under hypoxia by SN-38. Neither 5-FU nor oxaliplatin affected HIF-1α expression.
  
  
  CONCLUSIONS
  SN-38, through inhibition of HIF-1α can overcome chemoresistance under hypoxic conditions of colon cancer cells.
authors.affiliation: Department of Surgical Oncology, Faculty of Medical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. muronoksur@h.u-tokyo.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Murono
authors.forename: Nelson H
authors.initials: NH
authors.lastname: Tsuno
authors.forename: Kazushige
authors.initials: K
authors.lastname: Kawai
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Sasaki
authors.forename: Kumiko
authors.initials: K
authors.lastname: Hongo
authors.forename: Manabu
authors.initials: M
authors.lastname: Kaneko
authors.forename: Masaya
authors.initials: M
authors.lastname: Hiyoshi
authors.forename: Noriko
authors.initials: N
authors.lastname: Tada
authors.forename: Takako
authors.initials: T
authors.lastname: Nirei
authors.forename: Eiji
authors.initials: E
authors.lastname: Sunami
authors.forename: Koki
authors.initials: K
authors.lastname: Takahashi
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002453:Cell Cycle; D002455:Cell Division; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin