title: Preclinical evaluation of statins as a treatment for ovarian cancer.
abstract: OBJECTIVE
  To evaluate the potential for statins to treat ovarian cancer.
  
  
  METHODS
  The sensitivity of 7 ovarian cancer cell lines to either statins or statins combined with either carboplatin or paclitaxel was assessed using monolayer cultures. Sensitivity to simvastatin was also evaluated in ovarian cancer spheroids. The kinetics of cell death induced by simvastatin was evaluated by measuring Trypan Blue exclusion. Autophagy induced by simvastatin was assessed by measuring LC3-II, p62 or Rab7 by immunoblotting or immunocytochemistry.
  
  
  RESULTS
  All statins except pravastatin demonstrated single agent activity against monolayers (IC50=1-35 μM) and spheroids (IC50=1-13 μM). This was mediated by HMG-CoAR inhibition, because either mevalonate or geranylgeraniol prevented the cytotoxic effects of simvastatin. Continuous exposure for 4 days was necessary to cause cell death. Simvastatin caused accumulation of p62 but loss of Rab7, suggesting inhibition of autophagosome trafficking. Accumulation of LC3-II was also observed, even in the presence of bafilomycin, suggesting additional stimulation of an earlier step in autophagy. Knockdown of the key autophagy regulator Atg5 caused a modest increase in the sensitivity of Ovcar-8 cells to simvastatin. Finally, additive or mild antagonist effects were observed when simvastatin was combined simultaneously with either carboplatin or paclitaxel, but when cells were exposed to simvastatin prior to carboplatin, profound antagonism was observed.
  
  
  CONCLUSIONS
  These observations suggest that clinical trials of statins in ovarian cancer should evaluate high doses and schedules that ensure continual inhibition of HMG-CoAR. Simvastatin has conflicting effects on the autophagy pathway and this may contribute to its cytotoxic activity.
authors: 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
authors: Elizabeth
authors: E
authors: Robinson
authors: Mandrita
authors: M
authors: Nandi
authors: Laurelle L
authors: LL
authors: Wilkinson
authors: D Mark
authors: DM
authors: Arrowsmith
authors: Anthony D M
authors: AD
authors: Curtis
authors: Alan
authors: A
authors: Richardson
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016190:Carboplatin; D017239:Paclitaxel