Costunolide-Induced Apoptosis in Human Leukemia Cells: Involvement of c-Jun N-Terminal Kinase Activation

• Choi Jung-Hye

  Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University

• Lee Kyung-Tae

  Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University

抄録

The authors previously reported that costunolide, an active compound isolated from the stem bark of Magnolia sieboldii, induced apoptosis via reactive oxygen species (ROS) and Bcl-2-dependent mitochondrial permeability transition in human leukemia cells. In the present study, the authors investigated whether mitogen-activated protein kinases (MAPKs) are involved in the costunolide-induced apoptosis in human promonocytic leukemia U937 cells. Treatment with costunolide resulted in the significant activation of c-Jun N-terminal kinase (JNK), but not of extracellular-signal-related kinase (ERK1/2) or p38. In vitro kinase assays showed that JNK activity was low in untreated cells but increased dramatically after 30 min of costunolide treatment. U937 cells co-treated with costunolide and sorbitol, a JNK activator, exhibited higher levels of cell death. In addition, inhibition of the JNK pathway using a dominant-negative mutation of c-jun and JNK inhibitor SP600125, significantly prevented costunolide-induced apoptosis. Furthermore, pretreatment with the antioxidant NAC (N-acetyl-L-cysteine) blocked the costunolide-stimulated activation of JNK while the overexpression of Bcl-2 failed to reverse JNK activation. Pretreatment with SP600125 recovered the costunolide-suppressed Bcl-2 expression. These results indicate that costunolide-induced JNK activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (intraperitoneally once a day for 7 d) significantly suppressed tumor growth and increased survival in 3LL Lewis lung carcinoma-bearing model.

収録刊行物

• Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ

  Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ 32 (10), 1803-1808, 2009

  公益社団法人 日本薬学会

キーワード

• <i>Magnolia sieboldii</i>
• costunolide
• reactive oxygen species
• c-Jun-N-terminal kinase
• xenograft

詳細情報

• CRID: 1390001204624912896
• NII論文ID: 130000116947
• NII書誌ID: AA10885497
• DOI: 10.1248/bpb.32.1803
• ISSN: 13475215
• ISSN: 09186158
• NDL書誌ID: 10376018
• Web Site: http://id.ndl.go.jp/bib/10376018
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I10376018
• Web Site: http://www.jstage.jst.go.jp/article/bpb/32/10/32_10_1803/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2010089392
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可