title: Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species.
abstract: OBJECTIVE
  The acquired resistance to platinum-based drugs has become an obstacle in the management of ovarian cancer. We investigated the apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, in platinum-resistant human ovarian cancer cells, along with the molecular mechanism of action.
  
  
  METHODS
  Costunolide and cisplatin were examined in platinum-resistant human ovarian cancer cells. MTT assay for cell viability, PI staining for cell cycle profiling, and Annexin V assay for apoptosis analysis. ROS production and protein expression was assessed by H(2)DCFDA staining and Western blotting, respectively. Combination effect was determined using the Combination Index (CI) method.
  
  
  RESULTS
  It was found that costunolide is more potent than cisplatin in inhibiting cell growth in three platinum-resistant ovarian cancer cell lines (MPSC1(PT), A2780(PT), and SKOV3(PT)). Costunolide induced apoptosis of platinum-resistant cells in a time- and dose-dependent manner and suppressed tumor growth in SKOV3(PT)-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, -8, and -9. Pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Additionally, the antioxidant N-acetyl-L-cysteine (NAC) significantly attenuated the costunolide-induced production of ROS, activation of caspases, down-regulation of Bcl-2, and apoptosis in platinum-resistant ovarian cancer cells. Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.
  
  
  CONCLUSIONS
  Taken together, these data suggest that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancer.
authors.affiliation: Department of Life & Nanopharmaceutical Science, Kyung Hee University, Seoul, Republic of Korea.
authors.forename: Yeong-In
authors.initials: YI
authors.lastname: Yang
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009944:Organoplatinum Compounds / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D007783:Lactones
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020169:Caspases; D002945:Cisplatin; D009944:Organoplatinum Compounds; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C002602:costunolide; D007783:Lactones