title: Costunolide induces apoptosis in human endometriotic cells through inhibition of the prosurvival Akt and nuclear factor kappa B signaling pathway.
abstract: Endometriosis, a disease affecting 5-15% of women of reproductive age, is characterized by the ectopic growth of endometrial tissue. Costunolide, a sesquiterpene lactone, has anti-proliferative and pro-apoptotic activities that may be efficacious in therapy for endometriosis. In the present study, we investigated the effect of costunolide on the cell growth and apoptosis of endometriotic cells. We found that costunolide significantly inhibited the cell viability of 11Z and 12Z human endometriotic epithelial cells. Interestingly, endometriotic cells were more sensitive to costunolide treatment than immortalized endometrial cells (HES). Costunolide induced apoptosis of 11Z cells in a time-dependent manner as shown by accumulation of sub-G1 population. In addition, treatment with costunolide induced the activation of caspase-3, -8, and -9 in a dose- and time-dependent manner. Pretreatment with the broad caspase inhibitor z-VAD-fmk significantly reversed the costunolide-induced inhibition of cell viability in 11Z cells. We further demonstrated that costunolide inhibited the activation of Akt and nuclear factor kappa B (NFκB) and the expression of anti-apoptotic factors B-cell lymphoma-extra lage (Bcl-xL) and X-linked inhibitor of apoptosis protein (XIAP) in 11Z cells. These results suggest that costunolide induces apoptosis in human endometriotic epithelial cells by inhibiting the prosurvival NFκB and Akt pathway, leading to the downregulation of anti-apoptotic protein Bcl-xL and XIAP and the activation of caspases.
authors.affiliation: Department of Life & Nanopharamceutical Science, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Yeong-In
authors.initials: YI
authors.lastname: Yang
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Hee-Juhn
authors.initials: HJ
authors.lastname: Park
authors.forename: Jung-Hye
authors.initials: JH
authors.lastname: Choi
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004715:Endometriosis / Q000188:drug therapy* / Q000378:metabolism; D004717:Endometrium / Q000166:cytology / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors; D007783:Lactones
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D012717:Sesquiterpenes; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C002602:costunolide; D007783:Lactones