Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro

Lung cancer has the highest mortality rate worldwide and is often diagnosed at late stages, requiring genotoxic chemotherapy with significant side effects. Cancer prevention has become a major focus, including the use of dietary and supplemental antioxidants. Thus, we investigated the ability of an...

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Autores principales:	J.P. Jose Merlin, Graham Dellaire, Kieran Murphy, H.P. Vasantha Rupasinghe
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cancer chemoprevention gamma-H2AX flavonoids apple quercetin Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3a3d25f1ca474dedb25289f0a1facaf0
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spelling	oai:doaj.org-article:3a3d25f1ca474dedb25289f0a1facaf02021-11-25T16:50:29ZVitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro10.3390/biomedicines91116652227-9059https://doaj.org/article/3a3d25f1ca474dedb25289f0a1facaf02021-11-01T00:00:00Zhttps://www.mdpi.com/2227-9059/9/11/1665https://doaj.org/toc/2227-9059Lung cancer has the highest mortality rate worldwide and is often diagnosed at late stages, requiring genotoxic chemotherapy with significant side effects. Cancer prevention has become a major focus, including the use of dietary and supplemental antioxidants. Thus, we investigated the ability of an antioxidant formulation (AOX1) to reduce DNA damage in human bronchial epithelial cells (BEAS-2B) with and without the combination of apple peel flavonoid fraction (AF4), or its major constituent quercetin (Q), or Q-3-<i>O</i>-<span style="font-variant: small-caps;">d</span>-glucoside (Q3G) in vitro. To model smoke-related genotoxicity, we used cigarette-smoke hydrocarbon 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) as well as methotrexate (MTX) to induce DNA damage in BEAS-2B cells. DNA fragmentation, γ-H2AX immunofluorescence, and comet assays were used as indicators of DNA damage. Pre-exposure to AOX1 alone or in combination with AF4, Q, or Q3G before challenging with NNKOAc and MTX significantly reduced intracellular reactive oxygen species (ROS) levels and DNA damage in BEAS-2B cells. Although NNKOAc-induced DNA damage activated ATM-Rad3-related (ATR) and Chk1 kinase in BEAS-2B cells, pre-exposure of the cells with tested antioxidants prior to carcinogen challenge significantly reduced their activation and levels of γ-H2AX (<i>p</i> ≤ 0.05). Therefore, AOX1 alone or combined with flavonoids holds promise as a chemoprotectant by reducing ROS and DNA damage to attenuate activation of ATR kinase following carcinogen exposure.J.P. Jose MerlinGraham DellaireKieran MurphyH.P. Vasantha RupasingheMDPI AGarticlecancerchemopreventiongamma-H2AXflavonoidsapplequercetinBiology (General)QH301-705.5ENBiomedicines, Vol 9, Iss 1665, p 1665 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cancer chemoprevention gamma-H2AX flavonoids apple quercetin Biology (General) QH301-705.5
spellingShingle	cancer chemoprevention gamma-H2AX flavonoids apple quercetin Biology (General) QH301-705.5 J.P. Jose Merlin Graham Dellaire Kieran Murphy H.P. Vasantha Rupasinghe Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro
description	Lung cancer has the highest mortality rate worldwide and is often diagnosed at late stages, requiring genotoxic chemotherapy with significant side effects. Cancer prevention has become a major focus, including the use of dietary and supplemental antioxidants. Thus, we investigated the ability of an antioxidant formulation (AOX1) to reduce DNA damage in human bronchial epithelial cells (BEAS-2B) with and without the combination of apple peel flavonoid fraction (AF4), or its major constituent quercetin (Q), or Q-3-<i>O</i>-<span style="font-variant: small-caps;">d</span>-glucoside (Q3G) in vitro. To model smoke-related genotoxicity, we used cigarette-smoke hydrocarbon 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) as well as methotrexate (MTX) to induce DNA damage in BEAS-2B cells. DNA fragmentation, γ-H2AX immunofluorescence, and comet assays were used as indicators of DNA damage. Pre-exposure to AOX1 alone or in combination with AF4, Q, or Q3G before challenging with NNKOAc and MTX significantly reduced intracellular reactive oxygen species (ROS) levels and DNA damage in BEAS-2B cells. Although NNKOAc-induced DNA damage activated ATM-Rad3-related (ATR) and Chk1 kinase in BEAS-2B cells, pre-exposure of the cells with tested antioxidants prior to carcinogen challenge significantly reduced their activation and levels of γ-H2AX (<i>p</i> ≤ 0.05). Therefore, AOX1 alone or combined with flavonoids holds promise as a chemoprotectant by reducing ROS and DNA damage to attenuate activation of ATR kinase following carcinogen exposure.
format	article
author	J.P. Jose Merlin Graham Dellaire Kieran Murphy H.P. Vasantha Rupasinghe
author_facet	J.P. Jose Merlin Graham Dellaire Kieran Murphy H.P. Vasantha Rupasinghe
author_sort	J.P. Jose Merlin
title	Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro
title_short	Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro
title_full	Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro
title_fullStr	Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro
title_full_unstemmed	Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro
title_sort	vitamin-containing antioxidant formulation reduces carcinogen-induced dna damage through atr/chk1 signaling in bronchial epithelial cells in vitro
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3a3d25f1ca474dedb25289f0a1facaf0
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Vitamin-Containing Antioxidant Formulation Reduces Carcinogen-Induced DNA Damage through ATR/Chk1 Signaling in Bronchial Epithelial Cells In Vitro

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