title: Antagonism of Bcl-XL is necessary for synergy between carboplatin and BH3 mimetics in ovarian cancer cells.
abstract: BACKGROUND
  BH3 mimetics are a class of drugs that antagonize the Bcl-2 family of apoptosis inhibitors. We have previously shown that these compounds can potentiate the activity of carboplatin against several ovarian cancer cell lines. However, recent clinical studies have highlighted that BH3 mimetics which antagonise Bcl-XL are associated with significant thrombocytopenia. This has led to the development of ABT-199 which specifically inhibits Bcl-2. Unfortunately, Bcl-XL appears to be more frequently deregulated in ovarian cancer than Bcl-2. We therefore compared the ability of ABT-199, and the Bcl-XL selective compound WEHI-539, to potentiate the activity of carboplatin in ovarian cancer cell lines.
  
  
  METHODS
  WEHI-539, ABT-737 and ABT-199 were tested in combination with carboplatin using a panel of 6 ovarian cancer cell lines. The activity of the drugs was evaluated using cell growth assays, staining with trypan bue and measurement of apoptosis by measuring caspase 3/7 activity, PARP cleavage and annexin-V/propidium iodide staining.
  
  
  RESULTS
  We found that WEHI-539 and ABT-737, but not ABT-199, were synergistic with carboplatin in cell growth assays and potentiated cell death when assessed by trypan blue staining. Furthermore, WEHI-539 and ABT-737 augmented carboplatin induced caspase 3/7 activity, PARP cleavage and annexin V labelling, but ABT-199 failed to do so.
  
  
  CONCLUSIONS
  These observations suggest that compounds which target Bcl-XL are necessary if BH3 mimetics are to be successfully used to treat patients with ovarian cancer and this highlights the need to develop strategies to minimize thrombocytopenia induced by such compounds.
authors.affiliation: Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent, ST4 7QB, UK.
authors.forename: Mohammed Najim
authors.initials: MN
authors.lastname: Abed
authors.affiliation: Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent, ST4 7QB, UK.
authors.forename: Marwan Ibrahim
authors.initials: MI
authors.lastname: Abdullah
authors.affiliation: Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent, ST4 7QB, UK. a.richardson1@keele.ac.uk.|School of Pharmacy, Keele University, Keele, ST5 5BG, UK. a.richardson1@keele.ac.uk.
authors.forename: Alan
authors.initials: A
authors.lastname: Richardson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D018716:Molecular Mimicry; D009596:Nitrophenols / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010879:Piperazines / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009596:Nitrophenols; D010879:Piperazines; D013449:Sulfonamides; D051020:bcl-X Protein; D016190:Carboplatin; C579720:venetoclax
keywords: BH3 mimetics; Navitoclax; Ovarian cancer; Venetoclax