title: A small molecule SMAC mimic LBW242 potentiates TRAIL- and anticancer drug-mediated cell death of ovarian cancer cells.
abstract: BACKGROUND
  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 pro-apoptotic activity of LBW242, a mimic of SMAC/DIABLO, on ovarian cancer cell lines (A2780 cells and its chemoresistant derivative A2780/ADR, SKOV3 and HEY cells) and in primary ovarian cancer cells. The effects of LBW242 on ovarian cancer cell lines and primary ovarian cancer cells was determined by cell proliferation, apoptosis and biochemical assays.
  
  
  RESULTS
  LBW242 added alone elicited only a moderate pro-apoptotic effect; however, it strongly synergizes with tumor necrosis factor-related apoptosis inducing ligand (TRAIL) or anticancer drugs in inducing apoptosis of both ovarian cancer cell lines and primary ovarian cancer cells. Mechanistic studies show that LBW242-induced apoptosis in ovarian cancer cells is associated with activation of caspase-8. In line with this mechanism, c-FLIP overexpression inhibits LBW242-mediated apoptosis.
  
  
  CONCLUSIONS
  LBW242 sensitizes ovarian cancer cells to the antitumor effects of TRAIL and anticancer drugs commonly used in clinic. These observations suggest that the SMAC/DIABLO mimic LBW242 could be of value for the development of experimental strategies for treatment of ovarian cancer.
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Petrucci
authors.forename: Luca
authors.initials: L
authors.lastname: Pasquini
authors.forename: Manuela
authors.initials: M
authors.lastname: Bernabei
authors.forename: Ernestina
authors.initials: E
authors.lastname: Saulle
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.forename: Fabio
authors.initials: F
authors.lastname: Accarpio
authors.forename: Simone
authors.initials: S
authors.lastname: Sibio
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Violante
authors.initials: V
authors.lastname: Di Donato
authors.forename: Assunta
authors.initials: A
authors.lastname: Casorelli
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Benedetti-Panici
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
mesh_terms: D000704:Analysis of Variance; D017304:Annexin A5; D000970:Antineoplastic Agents / Q000378:metabolism*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D019772:Topotecan / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D017304:Annexin A5; D000970:Antineoplastic Agents; C522798:LBW242; D009842:Oligopeptides; D053221:TNF-Related Apoptosis-Inducing Ligand; D019772:Topotecan