Induction of apoptosis by citrus unshiu peel in human breast cancer MCF-7 cells: Involvement of ROS-Dependent activation of AMPK
Biological and Pharmaceutical Bulletin, ISSN: 1347-5215, Vol: 41, Issue: 5, Page: 713-721
2018
- 20Citations
- 29Captures
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Metrics Details
- Citations20
- Citation Indexes20
- 20
- CrossRef2
- Captures29
- Readers29
- 29
Article Description
The fruit of Citrus unshiu MARKOVICH used for various purposes in traditional medicine has various pharmacological properties including antioxidant, anti-inflammatory, and antibacterial effects. Recently, the possibility of anti-cancer activity of the extracts or components of this fruit has been reported; however, the exact mechanism has not yet been fully understood. In this study, we evaluated the anti-proliferative effect of water extract of C. unshiu peel (WECU) on human breast cancer MCF-7 cells and investigated the underlying mechanism. Our results showed that reduction of MCF-7 cell survival by WECU was associated with the induction of apoptosis. WECU-induced apoptotic cell death was related to the activation of caspase-8 and -9, representative initiate caspases of extrinsic and intrinsic apoptosis pathways, respectively, and increase in the Bax:Bcl-2 ratio accompanied by cleavage of poly(ADP-ribose) polymerase (PARP). WECU also increased the mitochondrial dysfunction and cytosolic release of cytochrome c. In addition, AMP-activated protein kinase (AMPK) and its downstream target molecule, acetyl-CoA carboxylase, were activated in a concentration-dependent manner in WECU-treated cells. In contrast, compound C, an AMPK inhibitor, significantly inhibited WECU-induced apoptosis, while inhibiting increased expression of Bax and decreased expression of Bcl-2 by WECU and inhibition of WECU-induced PARP degradation. Furthermore, WECU provoked the production of reactive oxygen species (ROS); however, the activation of AMKP and apoptosis by WECU were prevented, when the ROS production was blocked by antioxidant N-acetyl cysteine. Therefore, our data indicate that WECU suppresses MCF-7 cell proliferation by activating the intrinsic and extrinsic apoptosis pathways through ROS-dependent AMPK pathway activation.
Bibliographic Details
http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85046661616&origin=inward; http://dx.doi.org/10.1248/bpb.b17-00898; http://www.ncbi.nlm.nih.gov/pubmed/29709909; https://www.jstage.jst.go.jp/article/bpb/41/5/41_b17-00898/_article; https://www.jstage.jst.go.jp/article/bpb/41/5/41_b17-00898/_article/-char/en/; https://www.jstage.jst.go.jp/article/bpb/41/5/41_b17-00898/_article/-char/ja/; https://dx.doi.org/10.1248/bpb.b17-00898
Pharmaceutical Society of Japan
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