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Characterization of 4-O-methyl-ascochlorin-induced apoptosis in comparison with typical apoptotic inducers in human leukemia cell lines

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Abstract

Apoptosis can be induced by various stimuli such as the ligands of death receptors, chemotherapeutic drugs and irradiation. It is generally believed that chemotherapeutic drugs induce mitochondrial damage, cytochrome c release and activation of caspase-9, leading to apoptosis. Here, we found that an isoprenoid antibiotic, 4-O-methyl ascochlorin, significantly induces typical apoptotic events in Jurkat cells including the degradation of poly (ADP-ribose) polymerase, DNA fragmentation, activation of caspase-3, -9 and -8, and cytochrome c release from mitochondria. Similar to Fas stimulation, 4-O-methyl ascochlorin but not staurosporine, cycloheximide and actinomycin D, induced apoptosis in SKW6.4 cells, in which apoptosis is strongly dependent on death-inducing signaling-complex. Bcl-2 overexpression in Jurkat cells completely suppressed the apoptosis, but procaspase-9 processing was partially induced. A caspase-8 inhibitor, IETD-fmk, effectively suppressed poly (ADP-ribose) polymerase cleavage and cytochrome c release. However, 4-O-methyl ascochlorin induced apoptosis in Jurkat cells deficient of caspase-8 or Fas-associated death domain protein. These results suggest that 4-O-methyl ascochlorin induces apoptosis through the mechanism distinct from conventional apoptosis inducers.

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Authors and Affiliations

  1. Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa, Chiba, 277-0861, Japan

    M. Tsuruga, S. Ozawa & M. Togashi

  2. Department of Endocrine, Breast Surgery, Kyoto Prefectural University of Medicine, Kawaramachi, Hirokoji, Kamikyo-ku, Kyoto, 602-0841, Japan

    H. Nakajima

  3. Kidney Institute, Keimyung University School of Medicine, Daegu, 700-712, Republic of Korea

    Y.-C. Chang

  4. Nuclear Receptor Institute, KSP, 3-2-1 Sakado, Takatsu-ku, Kawasaki, 213-0012, Japan

    K. Ando

  5. Department of Biotechnology, Institute of Research and Innovation, 1201 Takada, Kashiwa, Chiba, 277-0861, Japan

    J. Magae

Authors
  1. M. Tsuruga
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  2. H. Nakajima
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  3. S. Ozawa
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  4. M. Togashi
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  5. Y.-C. Chang
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  6. K. Ando
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  7. J. Magae
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Correspondence to J. Magae.

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Tsuruga, M., Nakajima, H., Ozawa, S. et al. Characterization of 4-O-methyl-ascochlorin-induced apoptosis in comparison with typical apoptotic inducers in human leukemia cell lines. Apoptosis 9, 429–435 (2004). https://doi.org/10.1023/B:APPT.0000031456.09297.8f

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  • DOI: https://doi.org/10.1023/B:APPT.0000031456.09297.8f

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