title: Aryl Hydrocarbon Receptor Ligand 5F 203 Induces Oxidative Stress That Triggers DNA Damage in Human Breast Cancer Cells.
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.
authors.forename: Lancelot S
authors.initials: LS
authors.lastname: McLean
authors.forename: Cheri N
authors.initials: CN
authors.lastname: Watkins
authors.forename: Petreena
authors.initials: P
authors.lastname: Campbell
authors.forename: Dain
authors.initials: D
authors.lastname: Zylstra
authors.forename: Leah
authors.initials: L
authors.lastname: Rowland
authors.forename: Louisa H
authors.initials: LH
authors.lastname: Amis
authors.forename: Lia
authors.initials: L
authors.lastname: Scott
authors.forename: Crystal E
authors.initials: CE
authors.lastname: Babb
authors.forename: W Joel
authors.initials: WJ
authors.lastname: Livingston
authors.forename: Agus
authors.initials: A
authors.lastname: Darwanto
authors.forename: Willie L
authors.initials: WL
authors.lastname: Davis
authors.forename: Maheswari
authors.initials: M
authors.lastname: Senthil
authors.affiliation: ⊥Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, Galveston, Texas 77555, United States.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Sowers
authors.forename: Eileen
authors.initials: E
authors.lastname: Brantley
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D061986:MCF-7 Cells; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C425784:2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; D013844:Thiazoles; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases