title: A small molecule Smac mimic potentiates TRAIL-mediated cell death of ovarian cancer cells.
abstract: OBJECTIVE
  Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Second mitochondria derived activator of caspase (Smac) has been described to sensitize for apoptosis. We have explored the proapoptotic activity of a small molecule mimic of Smac/DIABLO on ovarian cancer cell lines (A2780 cells and its chemoresistant derivatives A2780/ADR and A2780/DDP), cancer cell lines and in primary ovarian cancer cells.
  
  
  METHODS
  The effects of a small molecule mimic of Smac/DIABLO on ovarian cancer cell lines and primary ovarian cancer cells were determined by cell proliferation, apoptosis and biochemical assays.
  
  
  RESULTS
  This compound added alone elicited only a weak proapoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or agonistic TRAILR2 antibody (Lexatumumab) in inducing apoptosis of ovarian cancer cells.
  
  
  CONCLUSIONS
  These observations suggest that small molecule mimic of Smac/DIABLO could be useful for the development of experimental strategies aiming to treat ovarian cancer. Interestingly, in addition to its well known proapoptotic effects, Smac/DIABLO elicited a significant increase of pro-caspase-3 levels.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Petrucci
authors.forename: Luca
authors.initials: L
authors.lastname: Pasquini
authors.forename: Alessia
authors.initials: A
authors.lastname: Petronelli
authors.forename: Ernestina
authors.initials: E
authors.lastname: Saulle
authors.forename: Gualtiero
authors.initials: G
authors.lastname: Mariani
authors.forename: Roberta
authors.initials: R
authors.lastname: Riccioni
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Ferretti
authors.forename: Pieluigi
authors.initials: P
authors.lastname: Benedetti-Panici
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Scambia
authors.forename: Robin
authors.initials: R
authors.lastname: Humphreys
authors.forename: Cesare
authors.initials: C
authors.lastname: Peschle
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D040761:Biomimetic Materials / Q000008:administration & dosage / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D053280:Diynes / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: C491032:1,6-bis(4,7-diaza-6-methyl-5-oxo-3-((2-((5-(phenylthio)tetrazol-1-yl)methyl)pyrrolidin-1-yl)carbonyl)octyloxy)-2,4-hexadiyne; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D053280:Diynes; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D013777:Tetrazoles; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D053148:Caspase 3; D053453:Caspase 9; C507357:mapatumumab