title: Characterisation and manipulation of docetaxel resistant prostate cancer cell lines.
abstract: BACKGROUND
  There is no effective treatment strategy for advanced castration-resistant prostate cancer. Although Docetaxel (Taxotere®) represents the most active chemotherapeutic agent it only gives a modest survival advantage with most patients eventually progressing because of inherent or acquired drug resistance. The aims of this study were to further investigate the mechanisms of resistance to Docetaxel. Three Docetaxel resistant sub-lines were generated and confirmed to be resistant to the apoptotic and anti-proliferative effects of increasing concentrations of Docetaxel.
  
  
  RESULTS
  The resistant DU-145 R and 22RV1 R had expression of P-glycoprotein and its inhibition with Elacridar partially and totally reversed the resistant phenotype in the two cell lines respectively, which was not seen in the PC-3 resistant sublines. Resistance was also not mediated in the PC-3 cells by cellular senescence or autophagy but multiple changes in pro- and anti-apoptotic genes and proteins were demonstrated. Even though there were lower basal levels of NF-κB activity in the PC-3 D12 cells compared to the Parental PC-3, docetaxel induced higher NF-κB activity and IκB phosphorylation at 3 and 6 hours with only minor changes in the DU-145 cells. Inhibition of NF-κB with the BAY 11-7082 inhibitor reversed the resistance to Docetaxel.
  
  
  CONCLUSIONS
  This study confirms that multiple mechanisms contribute to Docetaxel resistance and the central transcription factor NF-κB plays an immensely important role in determining docetaxel-resistance which may represent an appropriate therapeutic target.
authors: UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. amanda.oneill@ucd.ie
authors: Amanda J
authors: AJ
authors: O'Neill
authors: Maria
authors: M
authors: Prencipe
authors: Catherine
authors: C
authors: Dowling
authors: Yue
authors: Y
authors: Fan
authors: Laoighse
authors: L
authors: Mulrane
authors: William M
authors: WM
authors: Gallagher
authors: Darran
authors: D
authors: O'Connor
authors: Robert
authors: R
authors: O'Connor
authors: Aoife
authors: A
authors: Devery
authors: Claire
authors: C
authors: Corcoran
authors: Sweta
authors: S
authors: Rani
authors: Lorraine
authors: L
authors: O'Driscoll
authors: John M
authors: JM
authors: Fitzpatrick
authors: R William G
authors: RW
authors: Watson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D043823:Taxoids; D044005:Tetrahydroisoquinolines; D000077143:Docetaxel; D049410:Luciferases, Renilla; D001616:beta-Galactosidase; C083501:Elacridar