title: Docetaxel maintains its cytotoxic activity under hypoxic conditions in prostate cancer cells.
abstract: OBJECTIVE
  The efficacy of docetaxel has recently been shown to be increased under hypoxic conditions through the down-regulation of hypoxia-inducible-factor 1α (HIF1A). Overexpression of the hypoxia-responsive gene class III β-tubulin (TUBB3) has been associated with docetaxel resistance in a number of cancer models. We propose that administration of docetaxel to prostate patients has the potential to reduce the hypoxic response through HIF1A down-regulation and that TUBB3 down-regulation participates in sensitivity to docetaxel.
  
  
  METHODS
  The cytotoxic effect of docetaxel was determined in both 22Rv1 and DU145 prostate cancer cell lines and correlated with HIF1A expression levels under aerobic and hypoxic conditions. Hypoxia-induced chemoresistance was investigated in a pair of isogenic docetaxel-resistant PC3 cell lines. Basal and hypoxia-induced TUBB3 gene expression levels were determined and correlated with methylation status at the HIF1A binding site.
  
  
  RESULTS
  Prostate cancer cells were sensitive to docetaxel under both aerobic and hypoxic conditions. Hypoxic cytotoxicity of docetaxel was consistent with a reduction in detected HIF1A levels. Sensitivity correlated with reduced basal and hypoxia-induced HIF1A and TUBB3 expression levels. The TUBB3 HIF1A binding site was hypermethylated in prostate cell lines and tumor specimens, which may exclude transcription factor binding and induction of TUBB3 expression. However, acquired docetaxel resistance was not associated with TUBB3 overexpression.
  
  
  CONCLUSIONS
  These data suggest that the hypoxic nature of a tumor may have relevance as regard to their response to docetaxel. Further investigation into the nature of this relationship may allow identification of novel targets to improve tumor control in prostate cancer patients.
authors.affiliation: Prostate Molecular Oncology Research Group, Academic Unit of Clinical and Molecular Oncology, Institute of Molecular Medicine, St. James's Hospital and Trinity College Dublin, Dublin, Ireland.
authors.forename: James C
authors.initials: JC
authors.lastname: Forde
authors.forename: Antoinette S
authors.initials: AS
authors.lastname: Perry
authors.forename: Kevin
authors.initials: K
authors.lastname: Brennan
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Martin
authors.forename: Mark P
authors.initials: MP
authors.lastname: Lawler
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Lynch
authors.forename: Donal
authors.initials: D
authors.lastname: Hollywood
authors.forename: Laure
authors.initials: L
authors.lastname: Marignol
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology*; D014404:Tubulin / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C498585:TUBB3 protein, human; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel