title: Ellipticine induces apoptosis in human endometrial cancer cells: the potential involvement of reactive oxygen species and mitogen-activated protein kinases.
abstract: Ellipticine, an alkaloid isolated from Apocyanaceae plants, has been shown to exhibit antitumor activity in several human malignant tissues including breast, thyroid, and ovarian cancers. The antitumor activity of ellipticine is thought to be primarily mediated by the induction of DNA damage through the inhibition of topoisomerase II and formation of DNA adducts. The human endometrium is known to express topoisomerase II. However, the apoptogenic activity of ellipticine and the mechanisms underlying its action have not been investigated in endometrial cancer cells. In the present study, exposure to ellipticine (1-10μM) was shown to induce apoptosis in RL95-2 human endometrial cancer cells. Ellipticine-induced cell death was associated with the accumulation of cells in the G2/M phase of the cell cycle and was accompanied by depolarization of the mitochondrial membrane potential, release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondrial membrane, and caspase activation. The production of intracellular reactive oxygen species (ROS) was increased and sustained at high levels during ellipticine treatment. Subsequent to ROS accumulation, extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were activated in ellipticine-treated cells. Release of AIF from the mitochondria appeared to be affected by caspases, ROS, and ERK. The present data show that the treatment of RL95-2 cells with ellipticine induces apoptosis, ellipticine-induced apoptosis is mediated by ROS and the activation of MAPKs, and release of AIF is involved in a caspase-independent pathway. These results demonstrate the potential of ellipticine as a therapeutic strategy for the treatment of human endometrial cancers.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, Dong-A University, Busan 602-714, Republic of Korea.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Seung Gee
authors.initials: SG
authors.lastname: Lee
authors.forename: Jin-Yong
authors.initials: JY
authors.lastname: Chung
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Kim
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Park
authors.forename: Hyungjong
authors.initials: H
authors.lastname: Koh
authors.forename: Myoung Seok
authors.initials: MS
authors.lastname: Han
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Park
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004611:Ellipticines / Q000633:toxicity*; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D004611:Ellipticines; D017382:Reactive Oxygen Species; C034192:ellipticine; D020928:Mitogen-Activated Protein Kinases