title: The BH3 mimetic HA14-1 enhances 5-fluorouracil-induced autophagy and type II cell death in oesophageal cancer cells.
abstract: BACKGROUND
  Resistance to chemotherapeutic agents has been associated with a failure of cancer cells to induce apoptosis. Strategies to restore apoptosis have led to the development of BH3 mimetics, which inhibit anti-apoptotic Bcl-2 family members. We examined the sensitivity of three oesophageal cancer cell lines to 5-fluorouracil (5-FU) alone and in combination with the BH3 mimetic HA14-1.
  
  
  METHODS
  Clonogenic assays, morphology, markers of autophagy and apoptosis were used to assess the involved death mechanisms.
  
  
  RESULTS
  In response to 5-FU treatment, OE21 cells induce apoptosis, KYSE450 and KYSE70 cells are more resistant and induce autophagy accompanied by type II cell death. Autophagy induction results in ineffective treatment as substantial numbers of cells survive and re-populate. HA14-1 did not improve 5-FU treatment or reduce colony re-growth in the apoptosis deficient KYSE70 cells. However, the sensitivity of OE21 (apoptotic) and KYSE450 cells (apoptosis deficient/type II cell death) was significantly improved. In OE21 cells, treatment with 5-FU and HA14-1 resulted in augmentation of apoptosis. In KYSE450 cells, the reduction in recovering colonies following combination treatment was due to the enhancement of type II cell death.
  
  
  CONCLUSIONS
  The efficacy of HA14-1 is cell line dependent and is not reliant on apoptosis induction.
authors.affiliation: Leslie C Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute and Mercy University Hospital, University College Cork, Cork, Ireland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Nyhan
authors.forename: T R
authors.initials: TR
authors.lastname: O'Donovan
authors.forename: B
authors.initials: B
authors.lastname: Elzinga
authors.forename: L C
authors.initials: LC
authors.lastname: Crowley
authors.forename: G C
authors.initials: GC
authors.lastname: O'Sullivan
authors.forename: S L
authors.initials: SL
authors.lastname: McKenna
mesh_terms: D001343:Autophagy / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D009570:Nitriles / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D009570:Nitriles; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D005472:Fluorouracil