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Troxerutin subdues hepatic tumorigenesis via disrupting the MDM2–p53 interaction †
Food & Function ( IF 5.1 ) Pub Date : 2018-09-27 00:00:00 , DOI: 10.1039/c8fo01111g Nisha Susan Thomas 1, 2, 3 , Kiran George 2, 3, 4, 5 , Athavan Alias Anand Selvam 3, 6, 7, 8
Food & Function ( IF 5.1 ) Pub Date : 2018-09-27 00:00:00 , DOI: 10.1039/c8fo01111g Nisha Susan Thomas 1, 2, 3 , Kiran George 2, 3, 4, 5 , Athavan Alias Anand Selvam 3, 6, 7, 8
Affiliation
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Hepatocellular carcinoma (HCC) is the leading cause of cancer death worldwide that lacks proper medical prognosis and treatment. In the present study, the anti-tumoral potential of troxerutin (TX), an ethnomedicine, was examined in relation to its effects on the promoter 2-acetylaminofluorene (2-AAF) in N-nitrosodiethylamine (NDEA) initiated HCC, as compared to its effects on HCC induced by NDEA alone. Liver samples from each experimental group were collected and evaluated for histological, biochemical and cellular characterization. The protein expressions of apoptotic and cell proliferation markers were determined via immunohistochemistry and western blotting. Molecular docking was also performed to delineate the inhibitory mechanism of TX on HCC. The results show that only higher doses of TX showed a significant reduction in the incidence of hepatic nodule formation, and they also counteracted NDEA plus 2-AAF induced alterations in the enzymic status. The frequencies of glutathione-S-transferase and proliferating cell nuclear antigen, markers of S phase progression, were markedly reduced during TX treatment. TX also modulated the imbalance in the MDM2–p53 interaction. The molecular docking results confirmed the interaction of TX with the upstream kinases that regulate apoptosis. This study provides evidence that a copious dose of TX is required to counteract the differential mitoinhibitory effect of 2-AAF in NDEA initiated hepatomas, and TX exhibits an anti-tumoral effect via suppressing oxidative stress, regulating liver function enzymes, inhibiting inflammatory responses and modulating MDM2–p53 interactions, thus inducing apoptosis, and thereby suggesting that TX may provide promising therapeutic effects for the chemoprevention of HCC.
中文翻译：
Troxerutin通过破坏MDM2–p53相互作用来减轻肝癌的发生†
肝细胞癌（HCC）是全球癌症死亡的主要原因，缺乏适当的医学预后和治疗。在本研究中，相对于N-亚硝基二乙胺（NDEA）启动的HCC，研究了曲妥芦丁（TX）（一种民族药）的抗肿瘤潜力及其对启动子2-乙酰氨基芴（2-AAF）的影响。单独由NDEA诱导的肝癌的作用。收集每个实验组的肝脏样品，并对其组织学，生化和细胞特征进行评估。通过以下方法确定凋亡和细胞增殖标志物的蛋白质表达免疫组织化学和蛋白质印迹。还进行了分子对接以描述TX对HCC的抑制机制。结果表明，只有较高剂量的TX才显示肝结节形成的发生率显着降低，并且它们还抵消了NDEA加2-AAF诱导的酶状态改变。谷胱甘肽-S的频率TX治疗期间，S期进程的标志物-转移酶和增殖细胞核抗原显着降低。TX还调制了MDM2-p53相互作用中的不平衡。分子对接的结果证实了TX与调节细胞凋亡的上游激酶的相互作用。这项研究提供证据表明，需要大量剂量的TX来抵消2-AAF在NDEA引发的肝癌中的不同的线粒体抑制作用，并且TX通过抑制氧化应激，调节肝功能酶，抑制炎症反应和调节调制而表现出抗肿瘤作用。 MDM2-p53相互作用，从而诱导凋亡，从而提示TX可能为HCC的化学预防提供有希望的治疗作用。
更新日期：2018-09-27
中文翻译：
Troxerutin通过破坏MDM2–p53相互作用来减轻肝癌的发生†
肝细胞癌（HCC）是全球癌症死亡的主要原因，缺乏适当的医学预后和治疗。在本研究中，相对于N-亚硝基二乙胺（NDEA）启动的HCC，研究了曲妥芦丁（TX）（一种民族药）的抗肿瘤潜力及其对启动子2-乙酰氨基芴（2-AAF）的影响。单独由NDEA诱导的肝癌的作用。收集每个实验组的肝脏样品，并对其组织学，生化和细胞特征进行评估。通过以下方法确定凋亡和细胞增殖标志物的蛋白质表达免疫组织化学和蛋白质印迹。还进行了分子对接以描述TX对HCC的抑制机制。结果表明，只有较高剂量的TX才显示肝结节形成的发生率显着降低，并且它们还抵消了NDEA加2-AAF诱导的酶状态改变。谷胱甘肽-S的频率TX治疗期间，S期进程的标志物-转移酶和增殖细胞核抗原显着降低。TX还调制了MDM2-p53相互作用中的不平衡。分子对接的结果证实了TX与调节细胞凋亡的上游激酶的相互作用。这项研究提供证据表明，需要大量剂量的TX来抵消2-AAF在NDEA引发的肝癌中的不同的线粒体抑制作用，并且TX通过抑制氧化应激，调节肝功能酶，抑制炎症反应和调节调制而表现出抗肿瘤作用。 MDM2-p53相互作用，从而诱导凋亡，从而提示TX可能为HCC的化学预防提供有希望的治疗作用。
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