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

Lancelot S. McLean, Cheri N. Watkins, Petreena Campbell, Dain Zylstra, Leah Rowland, Louisa H. Amis, Lia Scott, Crystal E. Babb, W. Joel Livingston, Agus Darwanto, Willie L. Davis, Maheswari Senthil, Lawrence Sowers, Eileen Brantley

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. Pharmacological inhibition of AhR, JNK, or p38 attenuated 5F 203-mediated increases in intracellular ROS, apoptosis, and single-strand break formation. 5F 203 induced the expression of cytoglobin, an oxidative stress-responsive gene and a putative tumor suppressor, which was diminished with AhR, JNK, or p38 inhibition. Additionally, 5F 203-mediated increases in ROS production and cytoglobin were suppressed in AHR100 cells (AhR ligand-unresponsive MCF-7 breast cancer cells). Our data demonstrate 5F 203 induces ROS-mediated DNA damage at least in part via AhR, JNK, or p38 activation and modulates the expression of oxidative stress-responsive genes such as cytoglobin to confer its anticancer action.

Original languageEnglish (US)
Pages (from-to)855-871
Number of pages17
JournalChemical Research in Toxicology
Volume28
Issue number5
DOIs
StatePublished - May 18 2015

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Aryl Hydrocarbon Receptors
Oxidative stress
DNA Damage
Oxidative Stress
Cells
Breast Neoplasms
Ligands
DNA
Reactive Oxygen Species
Phosphotransferases
p38 Mitogen-Activated Protein Kinases
Tumors
2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole
Genes
Acetylcysteine
Chemical activation
JNK Mitogen-Activated Protein Kinases
Benzo(a)pyrene
Cell growth
Metabolites

ASJC Scopus subject areas

  • Toxicology

Cite this

McLean, L. S., Watkins, C. N., Campbell, P., Zylstra, D., Rowland, L., Amis, L. H., ... Brantley, E. (2015). Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells. Chemical Research in Toxicology, 28(5), 855-871. https://doi.org/10.1021/tx500485v

Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells. / McLean, Lancelot S.; Watkins, Cheri N.; Campbell, Petreena; Zylstra, Dain; Rowland, Leah; Amis, Louisa H.; Scott, Lia; Babb, Crystal E.; Livingston, W. Joel; Darwanto, Agus; Davis, Willie L.; Senthil, Maheswari; Sowers, Lawrence; Brantley, Eileen.

In: Chemical Research in Toxicology, Vol. 28, No. 5, 18.05.2015, p. 855-871.

Research output: Contribution to journalArticle

McLean, LS, Watkins, CN, Campbell, P, Zylstra, D, Rowland, L, Amis, LH, Scott, L, Babb, CE, Livingston, WJ, Darwanto, A, Davis, WL, Senthil, M, Sowers, L & Brantley, E 2015, 'Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells', Chemical Research in Toxicology, vol. 28, no. 5, pp. 855-871. https://doi.org/10.1021/tx500485v
McLean, Lancelot S. ; Watkins, Cheri N. ; Campbell, Petreena ; Zylstra, Dain ; Rowland, Leah ; Amis, Louisa H. ; Scott, Lia ; Babb, Crystal E. ; Livingston, W. Joel ; Darwanto, Agus ; Davis, Willie L. ; Senthil, Maheswari ; Sowers, Lawrence ; Brantley, Eileen. / Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells. In: Chemical Research in Toxicology. 2015 ; Vol. 28, No. 5. pp. 855-871.
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