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Diarylheptanoid hirsutenone enhances apoptotic effect of TRAIL on epithelial ovarian carcinoma cell lines via activation of death receptor and mitochondrial pathway

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Summary

Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) induces apoptosis in various cancer cells. Diarylheptanoids such as hirsutenone and oregonin have been shown to have anti-inflammatory and anti-tumor effects. However, it is still unknown by which mechanism diarylheptanoids induce cell death. In addition, the effect of hirsutenone on TRAIL-induced apoptosis in the human epithelial ovarian carcinoma cell lines is unknown. To assess the apoptosis promoting effect of hirsutenone, we investigated the effect of hirsutenone on the apoptotic effect of TRAIL using the human epithelial carcinoma cell lines OVCAR-3 and SK-OV-3. TRAIL induced nuclear damage, decrease in Bid, Bcl-2 and Bcl-xL protein levels, increase in Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (8, 9 and 3) and increase in tumor suppressor p53 levels. Hirsutenone enhanced the TRAIL-induced apoptosis-related protein activation, nuclear damage and cell death. The results suggest that hirsutenone may enhance the apoptotic effect of TRAIL on ovarian carcinoma cell lines by increasing the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated apoptotic pathway, leading to caspase activation. Hirsutenone may confer a benefit in the TRAIL treatment of epithelial ovarian adenocarcinoma.

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Acknowledgement

This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A085138).

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Authors and Affiliations

  1. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, South Korea

    Chung Soo Lee, Eun-Ra Jang & Yun Jeong Kim

  2. Department of Urology, Chung-Ang University Hospital, Seoul, 156-755, South Korea

    Soon Chul Myung

  3. Department of Microbiology, College of Medicine, Chung-Ang University, Seoul, 156-756, South Korea

    Wonyong Kim

  4. Pharmacognosy Laboratory, College of Pharmacy, Chung-Ang University, Seoul, 156-756, South Korea

    Min Won Lee

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  1. Chung Soo Lee
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Correspondence to Chung Soo Lee.

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Lee, C.S., Jang, ER., Kim, Y.J. et al. Diarylheptanoid hirsutenone enhances apoptotic effect of TRAIL on epithelial ovarian carcinoma cell lines via activation of death receptor and mitochondrial pathway. Invest New Drugs 30, 548–557 (2012). https://doi.org/10.1007/s10637-010-9601-5

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