Maayah Zaid H, Ghebeh Hazem, Alhaider Abdulqader A, El-Kadi Ayman O S, Soshilov Anatoly A, Denison Michael S, Ansari Mushtaq Ahmad, Korashy Hesham M
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Stem Cell & Tissue Re-Engineering, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Toxicol Appl Pharmacol. 2015 Apr 15;284(2):217-26. doi: 10.1016/j.taap.2015.02.007. Epub 2015 Feb 17.
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.
最近的研究表明，二甲双胍（MET）作为一种口服抗糖尿病药物，具有抗氧化活性，并且在几种致癌物诱导的动物模型和细胞系中对不同类型的癌症有效。然而，此前尚未有关于MET是否能预防乳腺癌的报道。因此，本研究的总体目标是阐明MET在非癌性人乳腺MCF10A细胞中的潜在化学预防作用，并探索其潜在机制，特别是细胞色素P4501A1（CYP1A1）/芳烃受体（AhR）途径的作用。使用AhR配体7,12-二甲基苯并[a]蒽（DMBA）将MCF10A细胞转化为具有DNA加合物形成的起始乳腺癌细胞。MET对DMBA诱导的乳腺癌发生的化学预防作用通过MET恢复碱基切除修复基因、8-氧代鸟嘌呤DNA糖基化酶（OGG1）和脱嘌呤/脱嘧啶内切核酸酶1（APE1）的mRNA水平诱导以及8-羟基-2'-脱氧鸟苷（8-OHdG）水平的能力得到证明。有趣的是，DMBA诱导的DNA加合物形成的抑制与CYP1A1和NAD(P)H：醌氧化还原酶1（NQO1）基因表达的成比例降低相关。从机制上讲，MET对DMBA诱导的CYP1A1和NQO1基因表达的抑制作用中AhR和核因子红细胞2相关因子2（Nrf2）的参与通过MET抑制DMBA诱导的外源性反应元件和抗氧化反应元件荧光素酶报告基因表达的能力得到证明，这表明存在AhR和Nrf2依赖性转录控制。然而，MET不能与AhR结合表明MET不是AhR配体。总之，目前的工作有力地证明，MET通过AhR配体非依赖性机制抑制CYP1A1的表达，从而抑制DMBA介导的致癌性和加合物形成。
