Caspase Inhibition Augmented Oridonin-Induced Cell Death in Murine Fibrosarcoma L929 by Enhancing Reactive Oxygen Species Generation

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概要

• 論文の詳細を見る

• Oridonin, a diterpenoid isolated from Rabdosia rubescences, has been reported to have antitumor effects. In this study, the growth-inhibitory activity of oridonin for L929 cells was exerted in a time-and dose-dependent manner. After treatment with oridonin for 24 h, L929 cells underwent both apoptosis and necrosis as measured by an lactate dehydrogenase (LDH) activity-based assay. A rapid generation of reactive oxygen species (ROS) was triggered by oridonin, and subsequently up-regulation of phospho-p53 (ser 15) expression and an increased expression ratio of Bax/Bcl-2 was observed. Furthermore, there was a significant fall in mitochondrial membrane potential (MMP) and increase in caspase-3 activity after exposure to oridonin for 24 h. Surprisingly, the pan-caspase inhibitor z-VAD-fmk and caspase3 inhibitor z-DEVD-fmk rendered L929 cells more sensitive to oridonin, rather than preventing oridonin-induced cell death. Oridonin and z-VAD-fmk co-treatment not only resulted in an even higher ROS production, but also made a more significant reduction in the MMP. Pretreatment of ROS scavenger N-acetylcysteine (NAC) led to a complete inhibition of oridonin-induced cell death, intracellular ROS generation, and MMP collapse. NAC treatment also reversed the potentiation of cell death by the pan-caspase inhibitor z-VAD-fmk. Taken together, these observations showed that oridonin-induced cell death in L929 cells involved intracellular ROS generation, activation of phospho-p53 (ser 15), and up-regulation of the Bax/Bcl-2 ratio; and the augmented cell death by z-VAD-fmk was dependent on an increased ROS production.

• 社団法人 日本薬理学会の論文
• 2008-09-20

著者

• Tashiro Shin-ichi

  Dep. Of Clinical And Biomedical Sciences Showa Pharmaceutical Univ. Jpn

• TASHIRO Shin-ichi

  Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University

• ONODERA Satoshi

  Department of Clinical and Biomedical Sciences, Showa Pharmaceutical University

• IKEJIMA Takashi

  China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical Unive

• Huang Jian

  Department Of Phytochemistry Shenyang Pharmaceutical University

• Yu Jinghua

  China-japan Research Institute Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical Univer

• Onodera S

  Dep. Of Clinical And Biomedical Sciences Showa Pharmaceutical Univ. Jpn

• Onodera Satoshi

  昭和薬科大学 病態科

• Ikejima Takashi

  China-japan Res. Inst. Of Medical And Pharmaceutical Sciences Shenyang Pharmaceutical Univ. Chn

• WU Jin-Nan

  China-Japan Research Institute of Medical Pharmaceutical Sciences, Shenyang Pharmaceutical Universit

• YANG Jia

  Department of Phytochemistry, Shenyang Pharmaceutical University

• Tashiro Shin-ichi

  Department Of Clinical And Biomedical Sciences Showa Pharmaceutical University

• Onodera Satoshi

  Department Of Cinical And Biomedical Sciences Showa Pharmaceutical University

• Tashiro Shin-ichi

  Department Of Cinical And Biomedical Sciences Showa Pharmaceutical University

• Tashiro S

  Department Of Clinical And Biomedical Sciences Showa Pharmaceutical University

• Onodera S

  Department Of Clinical And Biomedical Sciences Showa Pharmaceutical University

• Wu Jin-nan

  China-japan Research Institute Of Medical Pharmaceutical Sciences Shenyang Pharmaceutical University

• Huang Jian

  Department Of Hematology The First Affiliated Hospital College Of Medicine Zhejiang University

• Yang Jia

  Department Of Electrical Engineering National Chung-hsing University

• Yang Jia

  Department Of Phytochemistry Shenyang Pharmaceutical University

• Ikejima Takashi

  China–Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University

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