Department of Biochemistry, University of Madras, Guindy Campus, Chennai, India.
Chem Biol Interact. 2011 Aug 15;193(1):12-21. doi: 10.1016/j.cbi.2011.04.007. Epub 2011 Apr 30.
Hepatocellular carcinoma (HCC), a highly aggressive form of solid tumor, has been increasing in South East Asia. The lack of effective therapy necessitates the introduction of novel chemopreventive strategies to counter the substantial morbidity and mortality associated with the disease. Recently, we reported that dimethoxy flavone (DMF), a methylated flavone derived from chrysin, significantly suppressed the development of preneoplastic lesions induced by N-nitrosodiethylamine (DEN) in rats, although the mechanism of action was not known. In the present study, we have investigated the effects of DMF administration on gene expression changes related to the inflammation-mediated NF-kB pathway, Wnt pathway and apoptotic mediators in DEN-induced preneoplastic nodules. There was a significant increase in inflammatory markers like cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and a decrease in apoptotic mediators like p53, caspase-3 and bax in DEN-treated rats when compared to the control group. Activation of NF-kB was noticed by an elevated expression of nuclear protein expression of NF-kB and cytoplasmic phospho-IkBαSer(32/36) in the same animals. Likewise, upregulation of canonical Wnt pathway was noticed by elevated expression of nuclear protein levels of phospho-β-cateninThr(393) and cytoplasmic casein kinase-2 (CK2), Dvl2 and cyclin D1 levels, along with a simultaneous decrease in expression of phospho-GSK3β(Ser9). Dietary DMF (100mg/kg) administration inhibited liver nodule incidence and multiplicity by 82% and 78%, respectively. DMF also reversed the activation of NF-kB and Wnt pathway as shown by the decrease in protein expression of several proteins. Results of the present investigation provide evidence that attenuation of Wnt pathway and suppression of inflammatory response mediated by NF-kB could be implicated, in part, in the chemopreventive effects of methylated flavone. Therefore, the present findings hold great promise for the utilization of DMF as an effective chemotherapeutic agent in treating early stages of liver cancer.
肝细胞癌（HCC）是一种高度侵袭性的实体肿瘤，在东南亚地区呈上升趋势。由于缺乏有效的治疗方法，因此需要引入新的化学预防策略，以应对与该疾病相关的大量发病率和死亡率。最近，我们报道了二甲氧基黄酮（DMF），一种来源于白杨素的甲基化黄酮，可显著抑制 N-亚硝基二乙胺（DEN）诱导的大鼠前瘤病变的发展，尽管其作用机制尚不清楚。在本研究中，我们研究了 DMF 给药对 DEN 诱导的前瘤结节中与炎症介导的 NF-κB 途径、Wnt 途径和凋亡介质相关的基因表达变化的影响。与对照组相比，DEN 处理的大鼠中的炎症标志物（如环氧化酶-2（COX-2）和诱导型一氧化氮合酶（iNOS））显著增加，而凋亡介质（如 p53、caspase-3 和 bax）则减少。通过观察到核蛋白 NF-κB 的表达升高和相同动物细胞质磷酸化 IkBαSer（32/36）的升高，发现 NF-κB 被激活。同样，通过观察到核蛋白磷酸化-β-cateninThr（393）和细胞质酪蛋白激酶-2（CK2）、Dvl2 和细胞周期蛋白 D1 水平的升高以及磷酸化-GSK3β（Ser9）表达的同时降低，发现经典 Wnt 途径被上调。膳食 DMF（100mg/kg）给药分别抑制了 82%和 78%的肝结节发生率和多发性。DMF 还通过降低几种蛋白质的蛋白表达，逆转了 NF-κB 和 Wnt 途径的激活。本研究的结果提供了证据，表明 Wnt 途径的衰减和 NF-κB 介导的炎症反应的抑制可能部分涉及甲基化黄酮的化学预防作用。因此，本研究结果为 DMF 作为治疗肝癌早期阶段的有效化疗药物的应用提供了巨大的希望。
