title: The effect of oleuropein from olive leaf (Olea europaea) extract on Ca²⁺ homeostasis, cytotoxicity, cell cycle distribution and ROS signaling in HepG2 human hepatoma cells.
abstract: Oleuropein, a phenolic compound found in the olive leaf (Olea europaea), has been shown to have biological activities in different models. However, the effects of oleuropein on Ca(2+) homeostasis, cytotoxicity, cell cycle distribution and ROS signaling in liver cells have not been analyzed. Oleuropein induced [Ca(2+)]i rises only in HepG2 cells but not in AML12, HA22T or HA59T cells due to the different status of 3-hydroxy-3-methylglutaryl-CoA reductase expression. In HepG2 cells, this Ca(2+) signaling response was reduced by removing extracellular Ca(2+), and was inhibited by the store-operated Ca(2+) channel blockers 2-APB and SKF96365. In Ca(2+)-free medium, pretreatment with the ER Ca(2+) pump inhibitor thapsigargin abolished oleuropein-induced [Ca(2+)]i rises. Oleuropein induced cell cycle arrest which was associated with the regulation of p53, p21, CDK1 and cyclin B1 levels. Furthermore, oleuropein elevated intracellular ROS levels but reduced GSH levels. Treatment with the intracellular Ca(2+) chelator BAPTA-AM or the antioxidant NAC partially reversed oleuropein-induced cytotoxicity. Together, in HepG2 cells, oleuropein induced [Ca(2+)]i rises by releasing Ca(2+) from the ER and causing Ca(2+) influx through store-operated Ca(2+) channels. Moreover, oleuropein induced Ca(2+)-associated cytotoxicity that involved ROS signaling and cell cycle arrest. This compound may offer a potential therapy for treatment of human hepatoma.
authors.affiliation: Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
authors.forename: Jin-Shiung
authors.initials: JS
authors.lastname: Cheng
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi 613, Taiwan.
authors.forename: Chiang-Ting
authors.initials: CT
authors.lastname: Chou
authors.affiliation: Division of Trauma, Department of Emergency, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
authors.forename: Yuan-Yuarn
authors.initials: YY
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
authors.forename: Wei-Chih
authors.initials: WC
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan.
authors.forename: Pochuen
authors.initials: P
authors.lastname: Shieh
authors.affiliation: Department of Pharmacy, Tajen University, Pingtung 907, Taiwan.
authors.forename: Daih-Huang
authors.initials: DH
authors.lastname: Kuo
authors.affiliation: Department of Nursing, Tzu Hui Institute of Technology, Pingtung 907, Taiwan.
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Jan
authors.affiliation: Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan. Electronic address: lianggoole67@gmail.com.
authors.forename: Wei-Zhe
authors.initials: WZ
authors.lastname: Liang
mesh_terms: D002118:Calcium / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D056945:Hep G2 Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D057888:Iridoid Glucosides; D039823:Iridoids / Q000302:isolation & purification / Q000494:pharmacology*; D031658:Olea / Q000737:chemistry; D018515:Plant Leaves / Q000737:chemistry*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D057888:Iridoid Glucosides; D039823:Iridoids; D017382:Reactive Oxygen Species; C002769:oleuropein; D002118:Calcium
keywords: Apoptosis; Ca(2+); Cell cycle; Human hepatoma cells; Oleuropein; ROS