title: Paclitaxel and TRAIL synergize to kill paclitaxel-resistant small cell lung cancer cells through a caspase-independent mechanism mediated through AIF.
abstract: BACKGROUND
  Small cell lung cancer (SCLC) is the most aggressive form of lung cancer with poor disease outcome. The chemotherapeutic agent paclitaxel (PA) is commonly used as a second-line treatment in SCLC, but response rates are low.
  
  
  METHODS
  86M1 SCLC cells were treated in the presence or absence of paclitaxel and TRAIL or the combination for 24 hours. Western blot analysis was utilized to examine protein expression, cell surface protein expression and membrane integrity were elucidated by flow cytometry, and immunofluorescence microscopy was used to demonstrate translocation of proteins to the cell nucleus.
  
  
  RESULTS
  Human 86M1 SCLC cells were found to be resistant to PA killing in vitro. This resistance is mediated by up-regulation of pro-survival protein BCL-xl. However, PA also increases surface expression of death receptors 4 and 5 (DR4 and DR5, respectively). The death receptors' ligand increased SCLC killing by PA through an apparent caspase-independent route involving activation/translocation of AIF.
  
  
  CONCLUSIONS
  The addition of TRAIL to PA can potentiate apoptosis in a relatively PA-resistant SCLC line (specifically 86M1 cells). More importantly, we are the first to report an active method of resistance to paclitaxel in SCLC via BCL-xl up-regulation.
authors.affiliation: Immunology Program, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612, U.S.A.
authors.forename: Terri B
authors.initials: TB
authors.lastname: Hunter
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Manimala
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Luddy
authors.forename: Tracy
authors.initials: T
authors.lastname: Catlin
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Antonia
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D053218:Receptors, Death Domain; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D020169:Caspases; D017239:Paclitaxel