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Free Radic Biol Med. 2014 Feb;67:159-70. doi: 10.1016/j.freeradbiomed.2013.10.004. Epub 2013 Oct 17.

Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation.

Author information

1
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
2
Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
3
Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
4
Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
5
Center for Resources, Research, and Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Obstetrics & Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. Electronic address: tsaieing@yahoo.com.
6
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: hsuyl326@gmail.com.

Abstract

This study investigates the anticancer effect of arctigenin (ATG), a natural lignan product of Arctium lappa L., in human breast cancer MDA-MB-231 cells. Results indicate that ATG inhibits MDA-MB-231 cell growth by inducing apoptosis in vitro and in vivo. ATG triggers the mitochondrial caspase-independent pathways, as indicated by changes in Bax/Bcl-2 ratio, resulting in AIF and EndoG nuclear translocation. ATG increased cellular reactive oxygen species (ROS) production by increasing p22(phox)/NADPH oxidase 1 interaction and decreasing glutathione level. ATG clearly increases the activation of p38 MAPK, but not JNK and ERK1/2. Antioxidant EUK-8, a synthetic catalytic superoxide and hydrogen peroxide scavenger, significantly decreases ATG-mediated p38 activation and apoptosis. Blocking p38 with a specific inhibitor suppresses ATG-mediated Bcl-2 downregulation and apoptosis. Moreover, ATG activates ATF-2, a transcription factor activated by p38, and then upregulates histone H3K9 trimethylation in the Bcl-2 gene promoter region, resulting in Bcl-2 downregulation. Taken together, the results demonstrate that ATG induces apoptosis of MDA-MB-231 cells via the ROS/p38 MAPK pathway and epigenetic regulation of Bcl-2 by upregulation of histone H3K9 trimethylation.

KEYWORDS:

Apoptosis; Arctigenin; Breast cancer; Epigenetic; Free radicals; Oxidative stress; Phytoestrogen

[Indexed for MEDLINE]

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