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Food Chem Toxicol. 2018 Aug;118:154-167. doi: 10.1016/j.fct.2018.05.005. Epub 2018 May 6.

Myricetin-induced apoptosis of triple-negative breast cancer cells is mediated by the iron-dependent generation of reactive oxygen species from hydrogen peroxide.

Author information

1
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
2
Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
3
Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, Nova Scotia, Canada.
4
Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Surgery, Faculty of Medicine, Dalhousie University, Nova Scotia, Canada. Electronic address: d.w.hoskin@dal.ca.

Abstract

Myricetin is a dietary phytochemical with anticancer activity; however, the effect of myricetin on breast cancer cells remains unclear. Here, we show that myricetin inhibited the growth of triple-negative breast cancer (TNBC) cells but was less inhibitory for normal cells. The effect of myricetin was comparable to epigallocatechin gallate and doxorubicin, and greater than resveratrol and cisplatin. Myricetin-treated TNBC cells showed evidence of early and late apoptosis/necrosis, which was associated with intracellular reactive oxygen species (ROS) accumulation, extracellular regulated kinase 1/2 and p38 mitogen-activated protein kinase activation, mitochondrial membrane destabilization and cytochrome c release, and double-strand DNA breaks. The antioxidant N-acetyl-cysteine protected myricetin-treated TNBC cells from cytotoxicity due to DNA damage. Myricetin also induced hydrogen peroxide (H2O2) production in cell-free culture medium, as well as in the presence of TNBC cells and normal cells. In addition, deferiprone-mediated inhibition of intracellular ROS generation via the iron-dependent Fenton reaction and inhibition of extracellular ROS accumulation with superoxide dismutase plus catalase prevented myricetin-induced cytotoxicity in TNBC cell cultures. We conclude that the cytotoxic effect of myricetin on TNBC cells was due to oxidative stress initiated by extracellular H2O2 formed by autoxidation of myricetin, leading to intracellular ROS production via the Fenton reaction.

KEYWORDS:

Apoptosis; Breast cancer; Mitochondria; Myricetin; Oxidative stress

PMID:
29742465
DOI:
10.1016/j.fct.2018.05.005
[Indexed for MEDLINE]

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