title: Downregulation of AKT reverses platinum resistance of human ovarian             cancers in vitro.
abstract: Platinum resistance is the most crucial problem for treatment of ovarian             cancer. Increasing evidence points towards AKT overexpression as a mechanistic             reason for this clinical condition. The present study evaluates the effect of             overexpression and downregulation of AKT on the sensitivity to cisplatin in a             platinum-resistant human ovarian cancer cell line and the corresponding platinum-sensitive             parental cell line. A2780 and A2780cis ovarian cancer cell lines were stably transfected             with an AKT-sense and AKT-antisense plasmid. Successful transfection was evaluated             by western blot analysis. Cytotoxic effects of cisplatin were evaluated by metabolic             (MTT) and clonogenicity assays as well as by FACS analysis. AKT overexpression             (confirmed by western blotting) converted platinum-sensitive A2780 into platinum-resistant             cells as shown by MTT assay. Importantly, platinum resistance of A2780cis cells             could be reversed by downregulation of AKT, as demonstrated by MTT and clonogenicity             assays and FACS analysis. Our data provide strong evidence that cisplatin resistance             in ovarian cancer is mediated by AKT overexpression and can be overcome by AKT             downregulation, thus, providing a rationale for clinical phase II/III studies             combining AKT inhibitors with cisplatin.
authors.affiliation: Department of Gynecology, University of Würzburg, D-97080 Würzburg, Germany.
authors.forename: J C
authors.initials: JC
authors.lastname: Hahne
authors.forename: A
authors.initials: A
authors.lastname: Honig
authors.forename: S R
authors.initials: SR
authors.lastname: Meyer
authors.forename: S
authors.initials: S
authors.lastname: Gambaryan
authors.forename: U
authors.initials: U
authors.lastname: Walter
authors.forename: J
authors.initials: J
authors.lastname: Wischhusen
authors.forename: S F M
authors.initials: SF
authors.lastname: Häussler
authors.forename: S E
authors.initials: SE
authors.lastname: Segerer
authors.forename: N
authors.initials: N
authors.lastname: Fujita
authors.forename: J
authors.initials: J
authors.lastname: Dietl
authors.forename: J B
authors.initials: JB
authors.lastname: Engel
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017671:Platinum Compounds / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D017671:Platinum Compounds; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin