Daphnetin ameliorates 7,12-dimethylbenz[a] anthracene-induced mammary carcinogenesis through Nrf-2-Keap1 and NF-κB pathways
Daphnetin ameliorates 7,12-dimethylbenz[a] anthracene-induced mammary carcinogenesis through Nrf-2-Keap1 and NF-κB pathways
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DOI：
10.1016/j.biopha.2016.05.028
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发表时间：
2016-08-01
影响因子：
7.5
通讯作者：
Pattanayak, Shakti P.
中科院分区：
文献类型：
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作者：
Kumar, Abhishek;Jha, S.;Pattanayak, Shakti P.
癌症是一种主要与氧化失衡相结合的疾病。在乳腺癌中，氧化应激继而改变各种基因表达和信号通路，从而带来基因组的不稳定性和令人着迷的致癌突变。几种香豆素化合物具有抗多种恶性肿瘤的活性。其中，瑞香素(DAP)表现出宝贵的安全性和生物活性，有助于其抗癌疗效。本研究评价了DAP对7，12-二甲基苯并(A)菲(DMBA)诱发的雌性SD大鼠乳腺癌的抗氧化和化疗作用。此外，我们还确定了DAP对Keap1-NRF-2、相关的HO-1和NF-kappa B表达的影响，这些表达背后隐藏着抗氧化和抗增殖活性。在我们的研究结果中，DAP对对照组和实验组的脂质过氧化、血清、肝、肾和乳腺组织中的酶类(总超氧化物歧化酶、锰超氧化物歧化酶、铜锌超氧化物歧化酶、过氧化氢酶、GPX)和非酶类(GSH)抗氧化标志物均有保护作用。保护性NRF-2和HO-1表达上调，Keap1和NF-kappa B基因和蛋白表达同步抑制。DAP对p-AKT有抑制作用，但对p-ERK1/2无明显作用。DAP可通过多种机制抑制乳腺癌的发生。DAP对NRF-2-Keap1途径和核因子-kappaB表达的双重作用，为其在乳腺癌治疗中提供了潜在的化疗药物。(C)2016年爱思唯尔·马森SAS。版权所有。
Cancer is a faction of disorders that conjugated primarily with oxidative imbalance. In mammary carcinoma, oxidative stress secondarily changes various gene expressions and signalling pathways that bring genomic instability and mutagenic alterations that fascinating carcinogenesis. Several coumarin compounds are active against various malignancies. Among them, daphnetin (DAP) exhibits valuable safety and bioactivity profile that contributes towards its efficacy against cancer. In this study, the antioxidative and chemotherapeutic potential of DAP against 7,12-dimethylbenz(a) anthracene (DMBA)induced mammary carcinogenesis was evaluated in female Sprague-Dawley rats. Besides this, we have determined the effect of DAP on Keap1-Nrf-2, associated HO-1 and NF-kappa B expressions behind the antioxidative and anti-proliferating activity. In our findings, a protective effect of DAP was established against lipid peroxidation, enzymic (Total SOD, MnSOD, CuZnSOD, CAT, GPx) and non-enzymic (GSH) antioxidative markers in serum, liver, kidney and breast tissue of both control and experimental groups. An up-regulation of protective Nrf-2 & HO-1 with a synchronized suppression in Keap1 & NF-kappa B mRNA and protein expressions were observed. DAP revealed the inhibition of p-AKT which accountable for decrease in NF-kappa B expressions but shown to be ineffective on p-ERK1/2. This study revealed that DAP inhibits mammary carcinogenesis through multiple mechanisms. Dual efficacy of DAP on Nrf-2-Keap1 pathway and NF-kappa B expressions propose it as a potential chemotherapeutic agent in mammary cancer management. (C) 2016 Elsevier Masson SAS. All rights reserved.