Yang Yujie, Wang Yanran, Wang Ting, Jiang Xuehua, Wang Ling
Department of Clinical Pharmacy and Pharmacy Administration, West China School of Pharmacy, Sichuan University, Chengdu, China.
Department of Pharmacy, Sichuan Cancer Hospital and Institution, Sichuan Cancer Center, Chengdu, China.
Cell Biochem Funct. 2017 Dec;35(8):518-526. doi: 10.1002/cbf.3309. Epub 2017 Dec 7.
Nuclear factor (erythroid-derived 2)-like 2 (NRF2) regulates antioxidant enzymes and phase II detoxifying enzymes, such as NAD(P)H: quinone oxidoreductase 1 (NQO1). Modified Xiaoyao powder (MXP) is most frequently used in the prevention and treatment of breast cancer in China. This study aimed to screen active components of MXP for antioxidant stress and chemoprevention, which depend on NRF2-NQO1 signalling pathway. A total of 25 monomeric compounds contained in MXP were screened using an antioxidant response element-luciferase reporter. The most potent antioxidant response element-luciferase inducers were chosen to further examine their effects on NRF2 and NQO1 in MCF-7 cells. These results were then confirmed by determining the oxidative stress levels and chemopreventive effect on inhibiting carcinogenesis transformation in NRF2 knockdown (NRF2 ) and NRF2 wild-type MCF-10A cells. We found that quercetin, kaempferol, and atractylenolide II in MXP were potent NRF2 inducers, which could up-regulate the expression of NRF2 and its downstream enzymes NQO1. In addition, these components could decrease reduced oxidative stress and inhibit carcinogenesis transformation, which depended on NRF2-NQO1 pathway. In conclusion, NRF2-NQO1 pathway plays an essential role in mediating the activity of MXP and its active components, at least in part; some beneficial effects of MXP may be applicable to breast cancer chemoprevention. Our study firstly found MXP active components including quercetin, kaempferol, and atractylenolide II. Our results firstly demonstrate that NRF2-NQO1 pathway plays an essential role in mediating the activity of MXP and its active components in breast cancer chemoprevention. Our study firstly found that atractylenolide II is a novel NRF2 inducer.
核因子（红系衍生2）样2（NRF2）可调节抗氧化酶和Ⅱ相解毒酶，如NAD（P）H：醌氧化还原酶1（NQO1）。加味逍遥散（MXP）在中国最常用于乳腺癌的防治。本研究旨在筛选MXP中依赖NRF2-NQO1信号通路发挥抗氧化应激和化学预防作用的活性成分。利用抗氧化反应元件荧光素酶报告基因筛选出MXP中含有的25种单体化合物。选择最有效的抗氧化反应元件荧光素酶诱导剂，进一步研究它们对MCF-7细胞中NRF2和NQO1的影响。然后通过测定NRF2基因敲低（NRF2-）和NRF2野生型MCF-10A细胞中的氧化应激水平以及对抑制致癌转化的化学预防作用来证实这些结果。我们发现MXP中的槲皮素、山奈酚和白术内酯Ⅱ是有效的NRF2诱导剂，它们可以上调NRF2及其下游酶NQO1的表达。此外，这些成分可以降低氧化应激水平并抑制致癌转化，这依赖于NRF2-NQO1通路。总之，NRF2-NQO1通路在介导MXP及其活性成分的活性中至少部分发挥着重要作用；MXP的一些有益作用可能适用于乳腺癌的化学预防。我们的研究首次发现了MXP的活性成分，包括槲皮素、山奈酚和白术内酯Ⅱ。我们的结果首次证明NRF2-NQO1通路在介导MXP及其活性成分在乳腺癌化学预防中的活性方面发挥着重要作用。我们的研究首次发现白术内酯Ⅱ是一种新型的NRF2诱导剂。
