title: Anti-tumour activity of phosphoinositide-3-kinase antagonist AEZS-126 in models of ovarian cancer.
abstract: OBJECTIVE
  Platinum resistance is the most crucial problem for treatment of ovarian cancer. There is a clinical need for new treatment strategies which overcome platinum resistance. Recently high level of AKT was shown to be involved in platinum resistance and furthermore in resistance against Natural-killer (NK)-cell mediated killing in ovarian cancer.
  
  
  METHODS
  Here, we investigate the ability of the PI3K/AKT inhibitor AEZS-126 alone and in combination with rapamycin to selectively target ovarian cancer cell proliferation and survival in vitro by MTT-assays and FACS based analysis. Furthermore the mechanism of cytotoxicity is analysed by FACS based assays. The NK-killing efficiency of ovarian cancer cells with and without pre-treatment with AEZS-126 was analysed.
  
  
  RESULTS
  AEZS-126 showed good anti-tumour activity in in vitro models of ovarian cancer. Main mechanism of cytotoxicity seems to be necroptosis which could be abrogated by co-incubation with necrostatin-1. Furthermore pre-treatment of platinum resistant cells with AEZS-126 resulted in an increased accessibility of these tumour cells for killing by NK-cells.
  
  
  CONCLUSIONS
  We demonstrated the highly efficient anti-tumour activity of AEZS-126 in in vitro models of ovarian cancer. Due to the good anti-tumour activity and the expected increase in NK-cell mediated killing even of platinum resistant tumour cells, AEZS-126 seems to be a promising candidate for clinical testing in ovarian cancer.
authors.affiliation: Department of Gynecology, University Hospital of Würzburg, Josef-Schneider-Str. 4, 97080, Würzburg, Germany, hahnejen@yahoo.de.
authors.forename: Jens C
authors.initials: JC
authors.lastname: Hahne
authors.forename: Antje
authors.initials: A
authors.lastname: Kurz
authors.forename: Susanne R
authors.initials: SR
authors.lastname: Meyer
authors.forename: Johannes
authors.initials: J
authors.lastname: Dietl
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Engel
authors.forename: Arnd
authors.initials: A
authors.lastname: Honig
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; C507699:necrostatin-1