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

Allison Knickle; Wasundara Fernando; Anna L. Greenshields; H. P.Vasantha Rupasinghe; David W. Hoskin

doi:10.1016/j.fct.2018.05.005

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

Allison Knickle, Wasundara Fernando, Anna L. Greenshields, H. P.Vasantha Rupasinghe, David W. Hoskin

Research output: Contribution to journal › Article › peer-review

76 Citations (Scopus)

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.

Original language	English
Pages (from-to)	154-167
Number of pages	14
Journal	Food and Chemical Toxicology
Volume	118
DOIs	https://doi.org/10.1016/j.fct.2018.05.005
Publication status	Published - Aug 2018

Bibliographical note

Funding Information:
This study was supported by the Canadian Breast Cancer Foundation and the Queen Elizabeth II Foundation . AK was the recipient of a Trainee Award from the Beatrice Hunter Cancer Research Institute with funds provided by The Canadian Cancer Society, Nova Scotia Division as part of The Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR . WF is supported by the CIBC Graduate Scholarship in Medical Research and the DMRF Edward F. Crease Memorial Graduate Studentship in Cancer Research . VR holds the Killam Chair in Functional Foods and Nutraceuticals. DH is a Senior Scientist of the Beatrice Hunter Cancer Research Institute and holds the Canadian Breast Cancer Foundation-Atlantic Region Endowed Chair in Breast Cancer Research. The authors thank Dr. Karen Bedard for assistance with the Amplex Red ® assay.

Publisher Copyright:
© 2018 Elsevier Ltd

ASJC Scopus Subject Areas

Food Science
Toxicology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.fct.2018.05.005

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

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.",

author = "Allison Knickle and Wasundara Fernando and Greenshields, {Anna L.} and Rupasinghe, {H. P.Vasantha} and Hoskin, {David W.}",

note = "Funding Information: This study was supported by the Canadian Breast Cancer Foundation and the Queen Elizabeth II Foundation . AK was the recipient of a Trainee Award from the Beatrice Hunter Cancer Research Institute with funds provided by The Canadian Cancer Society, Nova Scotia Division as part of The Terry Fox Foundation Strategic Health Research Training Program in Cancer Research at CIHR . WF is supported by the CIBC Graduate Scholarship in Medical Research and the DMRF Edward F. Crease Memorial Graduate Studentship in Cancer Research . VR holds the Killam Chair in Functional Foods and Nutraceuticals. DH is a Senior Scientist of the Beatrice Hunter Cancer Research Institute and holds the Canadian Breast Cancer Foundation-Atlantic Region Endowed Chair in Breast Cancer Research. The authors thank Dr. Karen Bedard for assistance with the Amplex Red {\textregistered} assay. Publisher Copyright: {\textcopyright} 2018 Elsevier Ltd",

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AU - Rupasinghe, H. P.Vasantha

AU - Hoskin, David W.

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PY - 2018/8

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N2 - 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.

AB - 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.

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ER -

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

UN SDGs

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