Anti-cancerous effect of cis-khellactone from Angelica amurensis through the induction of three programmed cell deaths
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Samil Jung1,*, Hyung-In Moon2,*, Beom Suk Lee1,*, Subeen Kim1, Nguyen Thi Ngoc Quynh1, Jimin Yu2, Dan-Diem Thi Le1, Zolzaya Sandag1, Hyegyeong Lee1, Hyojeong Lee1, Nguyen Hai Anh1, Young Yang1, Jong-Seok Lim1, Keun-Il Kim1 and Myeong-Sok Lee1
1Department of Biological Science, Sookmyung Women's University, Seoul, 14310, South Korea
2Department of Medicinal Biotechnology, College of Health Sciences, Dong-A University, Busan, 49315, South Korea
*These authors have contributed equally to this work
Myeong-Sok Lee, email: [email protected]
Keywords: Angelica amurensis; cis-khellactone; anti-cancer drug; apoptosis, autophagy-mediated cell death; necrosis/necroptosis
Received: September 19, 2017 Accepted: February 27, 2018 Published: March 30, 2018
Angelica amurensis has traditionally been used to treat various medical problems. In this report, we introduce cis-khellactone as a new anti-cancer agent, which was isolated from the chloroform soluble fraction of the rhizomes of Angelica amurensis. Its anti-cancerous effect was at first tested in MCF7 and MDA-MB-231 breast cell lines, in which MCF7 is well known to be resistant to many anti-cancer drugs; MCF10A normal breast cell line was used as a control. In vitro experiments showed that cis-khellactone suppressed cell growth and proliferation at a relatively low concentrations (<5 μg/ml) and decreased cell viability at high concentrations (>10 μg/ml) in both cancer cell lines in a time- and concentration-dependent manner. This anti-cancerous effect was also checked in additional 16 different types of normal and cancer cell lines. Cis-khellactone treatment significantly suppressed cell proliferation and enhanced cell death in all tested cancer cell lines. Furthermore, Western blot analysis showed that cis-khellactone induced three types of programmed cell death (PCD): apoptosis, autophagy-mediated cell death, and necrosis/necroptosis. Cis-khellactone concentration-dependently decreased cell viability by increasing the level of reactive oxygen species (ROS) and decreasing mitochondrial membrane potential (MMP), which are related to all three types of PCD. Mitochondrial fractionation data revealed that cis-khellactone induced the translocation of BAX and BAK into mitochondria as well as the overexpression of VDAC1, which probably accelerates MMP disruption and finally cell death. Importantly, our extended in vivo studies with xenograft model further confirmed these findings of anti-cancerous effects and showed no harmful effects in normal tissues, suggesting that there would be no side effects in humans.
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