title: The cyclin-dependent kinase inhibitor p57(Kip2) is epigenetically regulated in carboplatin resistance and results in collateral sensitivity to the CDK inhibitor seliciclib in ovarian cancer.
abstract: BACKGROUND
  Carboplatin remains a first-line agent in the management of epithelial ovarian cancer (EOC). Unfortunately, platinum-resistant disease ultimately occurs in most patients. Using a novel EOC cell line with acquired resistance to carboplatin: PEO1CarbR, genome-wide micro-array profiling identified the cyclin-dependent kinase inhibitor p57(Kip2) as specifically downregulated in carboplatin resistance. Presently, we describe confirmation of these preliminary data with a variety of approaches.
  
  
  METHODS
  Cytotoxicity testing (MTT) and cell cycle blockade assessed drug responsiveness. Methylation specific PCR and pyrosequencing identified sites of promoter methylation in p57(Kip2). siRNA to p57(Kip2) was used to look at the changes in apoptosis of carboplatin treated EOC cells. EOC tissues (20 cases) were assessed for mRNA levels of p57(Kip2).
  
  
  RESULTS
  Carboplatin resistance was reversed using 5-aza-cytidine in vitro. Promoter methylation sites and preferential sensitivity to seliciclib were seen in PEO1CarbR cells. Silencing p57(Kip)2 decreased the apoptotic response to the effects of platinum but produced sensitisation to seliciclib. EOC biopsies indicated an association of high levels of p57(Kip2)mRNA with complete responses to chemotherapy and improved outcome.
  
  
  CONCLUSIONS
  We conclude that p57(Kip2) is a candidate biomarker of platinum sensitivity/resistance in EOC and such cases may show preferential response to the cyclin-dependent kinase inhibitor seliciclib.
authors.affiliation: Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. h.coley@surrey.ac.uk
authors.forename: H M
authors.initials: HM
authors.lastname: Coley
authors.forename: N A M
authors.initials: NA
authors.lastname: Safuwan
authors.forename: P
authors.initials: P
authors.lastname: Chivers
authors.forename: E
authors.initials: E
authors.lastname: Papacharalbous
authors.forename: T
authors.initials: T
authors.lastname: Giannopoulos
authors.forename: S
authors.initials: S
authors.lastname: Butler-Manuel
authors.forename: K
authors.initials: K
authors.lastname: Madhuri
authors.forename: D P
authors.initials: DP
authors.lastname: Lovell
authors.forename: T
authors.initials: T
authors.lastname: Crook
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D016190:Carboplatin / Q000627:therapeutic use; D045744:Cell Line, Tumor / Q000187:drug effects; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine
chemical_list: D000970:Antineoplastic Agents; D011687:Purines; D000077546:Roscovitine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016190:Carboplatin