title: Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells.
abstract: We have previously reported that calcium ionophore A23187 differentially induces necrosis in CEM cells, a T-lymphoblastic leukemia cell line, and apoptosis in HL60 cells, a promyelocytic leukemia cell line. Stimulation with VP16, however, induces typical apoptosis in both cell lines. Necrosis in CEM cells, characterized by cell shrinkage and clustering, began within 5 min of treatment. Swelling of the mitochondria, lumpy chromatin condensation and intact plasma membranes were evident by electron microscopy. These A23187-mediated changes in CEM cells were suppressed by clonazepam or CGP37157, inhibitors of the mitochondrial Na(+)/Ca(2+) exchanger. The changes, however, were not affected by cyclosporin A, an inhibitor of the mitochondrial permeability transition pore. In both CEM and HL60 cells, intra-cellular calcium increased with similar amplitude within 1 min of treatment with 2 microM A23187. Intra-mitochondrial calcium increased with clonazepam pre-treatment alone in both CEM and HL60 cells. However, intra-mitochondrial calcium did not change drastically in response to A23187 in CEM or HL60 cells, either untreated or pre-treated with clonazepam. A23187 induces necrosis in CEM cells concurrent with mitochondrial dysfunction, which is independent of the mitochondrial permeability transition, but affected by intra-mitochondrial calcium, while HL60 cells lack these early changes. Differences in the responses to A23187 between these two cell lines might derive from differences in the susceptibility of the mitochondrial membrane to rapid increases in intra-cellular calcium.
authors.affiliation: Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Hamahata
authors.forename: Souichi
authors.initials: S
authors.lastname: Adachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsubara
authors.forename: Masayuki
authors.initials: M
authors.lastname: Okada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Imai
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Shin-ya
authors.initials: SY
authors.lastname: Toyokuni
authors.forename: Masaki
authors.initials: M
authors.lastname: Ueno
authors.forename: Shigeo
authors.initials: S
authors.lastname: Wakabayashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Katanosaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akiba
authors.forename: Masaru
authors.initials: M
authors.lastname: Kubota
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000001:Calcimycin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002998:Clonazepam / Q000031:analogs & derivatives / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007476:Ionophores / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009336:Necrosis; D010740:Phospholipases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013841:Thiazepines / Q000494:pharmacology; D013997:Time Factors
chemical_list: D007476:Ionophores; D019253:Proto-Oncogene Proteins c-bcl-2; D013841:Thiazepines; D000001:Calcimycin; D002998:Clonazepam; C079032:CGP 37157; D016572:Cyclosporine; D010740:Phospholipases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002118:Calcium