Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Induction of Spontaneous Neutrophil Apoptosis by 4-O-Methyl-Ascochlorin, A Prenyl Phenol Compound

프레닐 페놀계 항생제인 4-O-methyl-ascochlorin에 의한 호중구 세포사멸의 유도

  • Son Dong-Aoon (Department of Biochemistry, College of Medicine, Dong-A University) ;
  • Lee Sun-Young (Medical Research Center for Cancer Molecular Therapy) ;
  • Lee Min-Jung (Medical Research Center for Cancer Molecular Therapy) ;
  • Park Joo-In (Medical Research Center for Cancer Molecular Therapy) ;
  • Hong Young-Seob (Department of Preventive Medicine, College of Medicine, Dong-A University) ;
  • Lee Yong-Hwan (Department of Preventive Medicine, Kosin University College of Medicine) ;
  • Chang Young-Chae (Department of Pathology, College of Medicine, Catholic University) ;
  • Kwak Jong-Young (Medical Research Center for Cancer Molecular Therapy)
  • 손동훈 (동아대학교 의과대학 생화학교실) ;
  • 이선영 (동아대학교 암분자치료연구센터) ;
  • 이민정 (동아대학교 암분자치료연구센터) ;
  • 박주인 (동아대학교 암분자치료연구센터) ;
  • 홍영습 (동아대학교 의과대학 예방의학교실) ;
  • 이용환 (고신의대 예방의학교실) ;
  • 장영채 (대구가톨릭의대 병리학교실) ;
  • 곽종영 (동아대학교 암분자치료연구센터)
  • Published : 2006.02.01
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Abstract

Neutrophils are short-lived leukocytes that play a vital role in immune responses to bacteria, yeast, and fungi. This study was performed to investigate the effect of 4-O-methyl-ascochlorin (MAC), an anti-tumor, antibiotic, and anti-fungal prenyl-phenol compound on the spontaneous apoptosis of human neutrophils. MAC time- and dose-dependently accelerated the spontaneous apoptosis of human neutrophils. The effect of MAC on neutrophil apoptosis was blocked by pre-treatment of the neutrophils with specific inhibitors of pancaspase (zVAD-fmk), caspase-8 (zIETD-fmk), or caspase-3 (zDEVD-fmk). The cleavage of procaspase-8 and procaspase-3 was increased by MAC. Mitochondrial permeability, which was measured by the retention of $DiOC_6(3)$, was dose-de-pendently increased by MAC but the change of mitochondrial permeability was not blocked by pretreatment of neutrophils with zIETD-fmk. These results suggest that MAC induces neutrophil apoptosis by caspase-8-dependent but mitochondria-independent manner.

호중구의 세포사멸은 자연적으로 일어나지만 여러 외부자극에 의한 신호의 전달에 의하여 증가하거나 지연된다. 본 연구에서는 항암, 항생제로 개발된 프레닐 페놀계인 ascochlorin의 유도체 중에서 백혈구 암의 세포사멸을 유도하는 4-O-methyl-ascochlorin (MAC)이 호중구의 자연 세포사멸 및 지연되는 세포사멸에 어떠한 영향을 미치는가와 그 작용기작을 연구하였다. 호중구의 세포사멸은 사람 말초 혈액으로부터 분리하여 세포 배양 시간에 따라 형태 변화, annexin-V/propidium iodide의 염색, 및 DNA 전기영동 등으로 조사하였다. MAC는 농도 및 시간 의존 형으로 호중구의 세포사멸을 증가시켰다. 그러나 granulocyte macrophage-colony stimulating factor나 lipopolysaccharide 등에 의한 세포사멸의 지연은 MAC에 의하여 부분적으로 억제되었다. MAC에 의한 세포사멸의 유도는 pancaspase, caspase-8 및 caspase-3 억제제인 zVAD-fmk. zIETD-fmk, 및 zDEVD-fmk에 의하여 억제되었으며 procaspase-8과 procaspase-3의 단백질 양도 MAC로 처리한 호중구에서 현저히 감소하였다. 미토콘드리아 막 투과성은 MAC에 의하여 현저히 감소하였으나 zVAD-fmk에 의하여 완전히 봉쇄되지 못하였다. 이들 결과 들은 MAC에 의한 호중구 세포사멸의 증가는 caspase-8 및 caspase-3의 활성을 통하여 일어나지만 미토콘드리아의 막성분에는 영향이 없다는 것을 제시하고 있다.

Keywords

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