Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells

Chemical Research in Toxicology
Lancelot McLeanEileen Brantley

Abstract

Breast tumors often show profound sensitivity to exogenous oxidative stress. Investigational agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) induces aryl hydrocarbon receptor (AhR)-mediated DNA damage in certain breast cancer cells. Since AhR agonists often elevate intracellular oxidative stress, we hypothesize that 5F 203 increases reactive oxygen species (ROS) to induce DNA damage, which thwarts breast cancer cell growth. We found that 5F 203 induced single-strand break formation. 5F 203 enhanced oxidative DNA damage that was specific to breast cancer cells sensitive to its cytotoxic actions, as it did not increase oxidative DNA damage or ROS formation in nontumorigenic MCF-10A breast epithelial cells. In contrast, AhR agonist and procarcinogen benzo[a]pyrene and its metabolite, 1,6-benzo[a]pyrene quinone, induced oxidative DNA damage and ROS formation, respectively, in MCF-10A cells. In sensitive breast cancer cells, 5F 203 activated ROS-responsive kinases: c-Jun-N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38). AhR antagonists (alpha-naphthoflavone, CH223191) or antioxidants (N-acetyl-l-cysteine, EUK-134) attenuated 5F 203-mediated JNK and p38 activation, depending on the cell type. Pha...Continue Reading

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Citations

Aug 16, 2018·Reviews on Environmental Health·Banrida Wahlang
May 17, 2017·Archives of Toxicology·Siva Kumar KolluriStephen Safe
Aug 23, 2019·Critical Reviews in Toxicology·Tian YangYing-Yong Zhao
Jan 31, 2020·Oxidative Medicine and Cellular Longevity·Abdullah M Alzahrani, Peramaiyan Rajendran
Feb 6, 2017·Environmental Science and Pollution Research International·Taymour MostafaBolis S Gendy
Nov 14, 2019·Medicinal Research Reviews·Jennifer R BakerAdam McCluskey
Nov 14, 2020·European Journal of Medicinal Chemistry·Derya OsmaniyeZafer Asım Kaplancıklı

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