Metformin inhibits 7,12-dimethylbenz[a]anthracene-induced breast carcinogenesis and adduct formation in human breast cells by inhibiting the cytochrome P4501A1/aryl hydrocarbon receptor signaling pathway

Journal Article · Wed Apr 15 04:00:00 EDT 2015 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2015.02.007· OSTI ID:22465738

Maayah, Zaid H. ^[1]; Ghebeh, Hazem ^[2]; Alhaider, Abdulqader A. ^[1]; El-Kadi, Ayman O.S. ^[3]; Soshilov, Anatoly A.; Denison, Michael S. ^[4]; Ansari, Mushtaq Ahmad ^[1]

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1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451 (Saudi Arabia)
2. Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Center, Riyadh 11211 (Saudi Arabia)
3. Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton (Canada)
4. Department of Environmental Toxicology, University of California at Davis, Davis, CA 95616 (United States)

Recent studies have established that metformin (MET), an oral anti-diabetic drug, possesses antioxidant activity and is effective against different types of cancer in several carcinogen-induced animal models and cell lines. However, whether MET can protect against breast cancer has not been reported before. Therefore, the overall objectives of the present study are to elucidate the potential chemopreventive effect of MET in non-cancerous human breast MCF10A cells and explore the underlying mechanism involved, specifically the role of cytochrome P4501A1 (CYP1A1)/aryl hydrocarbon receptor (AhR) pathway. Transformation of the MCF10A cells into initiated breast cancer cells with DNA adduct formation was conducted using 7,12-dimethylbenz[a]anthracene (DMBA), an AhR ligand. The chemopreventive effect of MET against DMBA-induced breast carcinogenesis was evidenced by the capability of MET to restore the induction of the mRNA levels of basic excision repair genes, 8-oxoguanine DNA glycosylase (OGG1) and apurinic/apyrimidinic endonuclease1 (APE1), and the level of 8-hydroxy-2-deoxyguanosine (8-OHdG). Interestingly, the inhibition of DMBA-induced DNA adduct formation was associated with proportional decrease in CYP1A1 and in NAD(P)H:quinone oxidoreductase 1 (NQO1) gene expression. Mechanistically, the involvements of AhR and nuclear factor erythroid 2-related factor-2 (Nrf2) in the MET-mediated inhibition of DMBA-induced CYP1A1 and NQO1 gene expression were evidenced by the ability of MET to inhibit DMBA-induced xenobiotic responsive element and antioxidant responsive element luciferase reporter gene expression which suggests an AhR- and Nrf2-dependent transcriptional control. However, the inability of MET to bind to AhR suggests that MET is not an AhR ligand. In conclusion, the present work shows a strong evidence that MET inhibits the DMBA-mediated carcinogenicity and adduct formation by inhibiting the expression of CYP1A1 through an AhR ligand-independent mechanism. - Highlights: • Metformin (MET) protects against DMBA-induced DNA adduct and oxidative stress in human breast MCF10A cells. • MET inhibits DMBA-induced CYP1A1 gene expression through XRE-dependent mechanism. • MET inhibits DMBA-induced NQO1 gene expression through ARE-dependent mechanism. • MET did not displace [{sup 3}H]-TCDD from its binding site while successfully inhibited the nuclear translocation of AhR. • MET is not an AhR ligand.

• OSTI ID: 22465738
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 284; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTHRACENE
ANTIOXIDANTS
CARCINOGENESIS
DIMETHYLBENZANTHRACENE
DNA
DNA ADDUCTS
DNA DAMAGES
EXCISION REPAIR
GENES
INHIBITION
LIGANDS
LUCIFERASE
MAMMARY GLANDS
MESSENGER-RNA
NAD
NEOPLASMS
OXIDATION
RECEPTORS
SIGNALS