title: Synergistic effects of the sesquiterpene lactone, EPD, with cisplatin and paclitaxel in ovarian cancer cells.
abstract: BACKGROUND
  Ovarian cancer remains still the leading cause of death of gynecological malignancy, in spite of first-line chemotherapy with cisplatin and paclitaxel. Although initial response is favorably, relapses are common and prognosis for women with advanced disease stays poor. Therefore efficacious approaches are needed.
  
  
  METHODS
  Previously, an anti-cancer agent, EPD exhibited potent cytotoxic effects towards ovarian cancer and not towards normal cells. Cell viability and cell cycle analysis studies were performed with EPD, in combination with cisplatin and/or paclitaxel, using the ovarian carcinoma cell lines: SK-OV-3, OVCAR-3, JC, JC-pl and normal fibroblasts. Cell viability was measured using Presto Blue and cell cycle analysis using a flow cytometer. Apoptosis was measured in JC and JC-pl , using the caspase 3 assay kit.
  
  
  RESULTS
  In JC-pl, SK-OV-3 and JC, synergistic interactions between either EPD and cisplatin or EPD and paclitaxel were observed. For the first time the effects of EPD on the cell cycle of ovarian cancer cells and normal cells was studied. EPD and combinations of EPD with cisplatin and/ or paclitaxel showed cell cycle arrest in the G2/M phase. The combination of EPD and cisplatin showed a significant synergistic effect in cell line JC-pl, while EPD with paclitaxel showed synergistic interaction in JC. Additionally, synergistic drug combinations showed increased apoptosis.
  
  
  CONCLUSIONS
  Our results showed a synergistic effect of EPD and cisplatin in an ovarian drug resistant cell line as well as a synergistic effect of EPD and paclitaxel in two other ovarian cell lines. These results might enhance clinical efficacy, compared to the existing regimen of paclitaxel and cisplatin.
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. carocell@planet.nl.
authors.forename: Caroline
authors.initials: C
authors.lastname: van Haaften
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. A.Boot@lumc.nl.
authors.forename: Arnoud
authors.initials: A
authors.lastname: Boot
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. W.E.Corver@lumc.nl.
authors.forename: Willem E
authors.initials: WE
authors.lastname: Corver
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. J.D.H.van_Eendenburg@lumc.nl.
authors.forename: Jaap D H
authors.initials: JD
authors.lastname: van Eendenburg
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. J.B.M.Z.Trimbos@lumc.nl.
authors.forename: Baptist J M Z
authors.initials: BJ
authors.lastname: Trimbos
authors.affiliation: Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. T.van_Wezel@lumc.nl.
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007783:Lactones / Q000627:therapeutic use*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D012717:Sesquiterpenes; D017239:Paclitaxel; D002945:Cisplatin