title: PRIMA-1(MET) induces death in soft-tissue sarcomas cell independent of p53.
abstract: BACKGROUND
  The aim of this study was to explore the efficacy and define mechanisms of action of PRIMA-1(MET) as a TP53 targeted therapy in soft-tissue sarcoma (STS) cells.
  
  
  METHODS
  We investigated effects of PRIMA-1(MET) on apoptosis, cell cycle, and induction of oxidative stress and autophagy in a panel of 6 STS cell lines with different TP53 status.
  
  
  RESULTS
  Cell viability reduction by PRIMA-1(MET) was significantly observed in 5 out of 6 STS cell lines. We found that PRIMA-1(MET) was capable to induce cell death not only in STS cells harboring mutated TP53 but also in TP53-null STS cells demonstrating that PRIMA-1(MET) can induce cell death independently of TP53 in STS cells. We identified an important role of reactive oxygen species (ROS), involved in PRIMA-1(MET) toxicity in STS cells leading to a caspase-independent cell death. ROS toxicity was associated with autophagy induction or JNK pathway activation which represented potential mechanisms of cell death induced by PRIMA-1(MET) in STS.
  
  
  CONCLUSIONS
  PRIMA-1(MET) anti-tumor activity in STS partly results from off-target effects involving ROS toxicity and do not deserve further development as a TP53-targeted therapy in this setting.
authors.affiliation: National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France. t.grellety@bordeaux.unicancer.fr.|University of Bordeaux, Bordeaux, France. t.grellety@bordeaux.unicancer.fr.|Department of Medical Oncology, Institut Bergonié, Bordeaux, France. t.grellety@bordeaux.unicancer.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grellety
authors.affiliation: National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France. a.laroche-clary@bordeaux.unicancer.fr.|University of Bordeaux, Bordeaux, France. a.laroche-clary@bordeaux.unicancer.fr.
authors.forename: Audrey
authors.initials: A
authors.lastname: Laroche-Clary
authors.affiliation: National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France. v.chaire@bordeaux.unicancer.fr.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Chaire
authors.affiliation: National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France. p3.lagarde@bordeaux.unicancer.fr.|University of Bordeaux, Bordeaux, France. p3.lagarde@bordeaux.unicancer.fr.|Department of Pathology, Institut Bergonié, Bordeaux, France. p3.lagarde@bordeaux.unicancer.fr.
authors.forename: Pauline
authors.initials: P
authors.lastname: Lagarde
authors.affiliation: National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France. f.chibon@bordeaux.unicancer.fr.|Department of Pathology, Institut Bergonié, Bordeaux, France. f.chibon@bordeaux.unicancer.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chibon
authors.affiliation: National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France. a.neuville@bordeaux.unicancer.fr.|University of Bordeaux, Bordeaux, France. a.neuville@bordeaux.unicancer.fr.|Department of Pathology, Institut Bergonié, Bordeaux, France. a.neuville@bordeaux.unicancer.fr.
authors.forename: Agnes
authors.initials: A
authors.lastname: Neuville
authors.affiliation: National Institute of Health and Medical research, INSERM U916, Institut Bergonié, Bordeaux, France. a.italiano@bordeaux.unicancer.fr.|Department of Medical Oncology, Institut Bergonié, Bordeaux, France. a.italiano@bordeaux.unicancer.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011812:Quinuclidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D011812:Quinuclidines; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C533410:eprenetapopt