Costunolide-Induced Apoptosis Is Caused by Receptor-Mediated Pathway and Inhibition of Telomerase Activity in NALM-6 Cells(Pharmacology)

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概要

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• Costunolide, isolated from the stem bark of Magnolia sieboldii, is a sesquiterpene lactone that exhibits various biological and immunological actions. We investigated the induction mechanism of apoptosis by costunolide in a human B cell leukemia NALM-6 cell culture system. Costunolide (10 μM)-induced apoptosis time-dependently increased, estimated by nuclear damage observation and flow cytometric analysis. Costunolide did not change Fas-associated factor 1 (FAF1), but the phosphorylation of Fas-associated death domain (FADD) at serine 194 increased from early treatment. The activation of caspase-8 and -9 and degradation of poly-(ADP-ribose) polymerase (PARP) was time-dependently detected by incubation with costunolide. Pretreatment of cells with caspase-3, -8 and broad spectrum caspase inhibitors significantly blocked costunolide-induced apoptosis, but caspase-9 inhibitor failed to block apoptosis. Telomerase activity was significantly suppressed after treatment with costunolide, and human telomerase reverse transcriptase (hTERT), a critical determinant of the enzyme activity of telomerase, decreased the expression of both mRNA and protein levels by costunolide. Costunolide-induced repression of telomerase was prevented by pretreatment of cells with caspase-3, -8 and broad spectrum caspase inhibitors, but caspase-9 inhibitor was no effect. These data suggest that one of the costunolide-induced apoptotic mechanisms is that the receptor-mediated pathway precedes the mitochondria-dependent pathway, caused by the inhibition of telomerase activity via suppression of hTERT in NALM-6 cells.

• 2008-05-01

著者

• ISHIKAWA Masaaki

  Department of Pharmacology and Toxicology, Cancer Research Institute, Tohoku Pharmaceutical Universi

• KANNO Syu-ichi

  Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University

• KITAJIMA Yasue

  Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University

• KAKUTA Mai

  Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University

• OSANAI Yuu

  Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University

• KURAUCHI Kaori

  Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University

• UJIBE Mayuko

  Department of Clinical Pharmacotherapeutics, Tohoku Pharmaceutical University

• Kakuta Mai

  Department Of Clinical Pharmacotherapeutics Tohoku Pharmaceutical University

• Osanai Yuu

  Department Of Clinical Pharmacotherapeutics Tohoku Pharmaceutical University

• Ujibe Mayuko

  Department Of Clinical Pharmacotherapeutics Tohoku Pharmaceutical University

• Kanno Syu-ichi

  Department Of Clinical Pharmacotherapeutics Tohoku Pharmaceutical University

• Kanno Syu-ichi

  東北薬科大学癌研究所

• Kimura Katsuhiko

  Department Of Clinical Pharmacotherapeutics Tohoku Pharmaceutical University

• Kitajima Yasue

  Department Of Clinical Pharmacotherapeutics Tohoku Pharmaceutical University

• Kanno Syu-ichi

  東北薬科大学 薬物治療学教室

• Kanno Syu-ichi

  Department Of Pharmacology And Toxicology Cancer Research Institute Tohoku Pharmaceutical University

• Ishikawa Masaaki

  Department Of Clinical Pharmacotherapeutics Tohoku Pharmaceutical University

• Ishikawa Masaaki

  Department Of Pharmacology And Toxicology Cancer Research Institute Tohoku Pharmaceutical University

• Ishikawa Masaaki

  Department Of Pharmacology And Toxicology Cancer Research Institute Tohoku College Of Pharmacy

• Koiwai Kimiko

  Department Of Pharmacology And Toxicology Cancer Research Institute Tohoku Pharmaceutical University

• Ishikawa Masaaki

  Dep. Of Clinical Pharmacotheraputics Tohoku Pharmaceutical Univ. Jpn

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