Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells

Keigo Hamahata, Souichi Adachi, Hiroshi Matsubara, Masayuki Okada, Tsuyoshi Imai, Ken Ichiro Watanabe, Shin Ya Toyokuni, Masaki Ueno, Shigeo Wakabayashi, Yuki Katanosaka, Satoshi Akiba, Masaru Kubota, Tatsutoshi Nakahata

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19 Citations (Scopus)

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+/Ca2+ 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 μM 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.

Original languageEnglish
Pages (from-to)187-196
Number of pages10
JournalEuropean Journal of Pharmacology
Volume516
Issue number3
DOIs
Publication statusPublished - Jun 15 2005
Externally publishedYes

Keywords

  • Apoptosis
  • Bcl-2
  • Calcium ionophore
  • Clonazepam
  • Mitochondria
  • Necrosis

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Hamahata, K., Adachi, S., Matsubara, H., Okada, M., Imai, T., Watanabe, K. I., Toyokuni, S. Y., Ueno, M., Wakabayashi, S., Katanosaka, Y., Akiba, S., Kubota, M., & Nakahata, T. (2005). Mitochondrial dysfunction is related to necrosis-like programmed cell death induced by A23187 in CEM cells. European Journal of Pharmacology, 516(3), 187-196. https://doi.org/10.1016/j.ejphar.2005.04.018