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首页> 外文期刊>Journal of biochemical and molecular toxicology >Apoptosis oxidative damage-mediated and antiproliferative effect of selenylated imidazo[1,2-a]pyridines on hepatocellular carcinoma HepG2 cells and in vivo
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Apoptosis oxidative damage-mediated and antiproliferative effect of selenylated imidazo[1,2-a]pyridines on hepatocellular carcinoma HepG2 cells and in vivo

机译：凋亡氧化损伤介导和抗增殖效应的亚苯基化咪唑[1,2-a]吡啶对肝细胞癌Hepg2细胞和体内的抗增殖作用

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摘要

lmidazo[1,2-a]pyridines (IP) and organoselenium compounds have been widely exploited in medicinal chemistry due to their pharmacological activities. Hepatocellular carcinoma (HCC) has few treatment options, and unfortunately, the prognosis is poor. Thus, the development of novel therapeutic drugs is urgent. The present study aimed at evaluating the antitumor mechanism of selenylated IP against HepG2 cells and in vivo. The selenylated IP named IP-Se-06 (3-((2-methoxyphenyl)selanyl)-7-methyl-2-phenylimidazol[1,2-a]pyridine) showed high cytotoxicity against HepG2 cells (half-maximal inhibitory concentration [IC_50] = 0.03 muM) and selectivity for this tumor cell line. At nontoxic concentration, IP-Se-06 decreased the protein levels of Bcl-xL and increased the levels of p53, leading to inhibition of cell proliferation and apoptosis. This compound decreased the level of extracellular signal-regulated kinase 1/2 protein and changed the levels of proteins involved in the drive of the cell cycle, tumor growth, and survival (cyclin B1, cyclin-dependent kinase 2). In addition, IP-Se-06 decreased the number of cells in the S phase. In addition, IP-Se-06 led to increased generation of reactive oxygen species, changed antioxidant defenses, and caused DNA fragmentation. Finally, IP-Se-06 significantly inhibited the growth of Ehrlich ascites tumors in mice, increased survival time, and inhibited angiogenesis. Therefore, IP-Se-06 may be an important compound regarding the development of a therapeutic drug for HCC treatment.
机译：lmidazo[1,2-a]吡啶（IP）和有机硒化合物因其药理活性在药物化学中得到了广泛的应用。肝细胞癌（HCC）几乎没有治疗选择，不幸的是，预后很差。因此，开发新型治疗药物迫在眉睫。本研究旨在评估硒化IP对HepG2细胞的抗肿瘤机制以及在体内的作用。名为IP-Se-06（3-（（2-甲氧基苯基）selanyl）-7-甲基-2-苯基咪唑[1,2-a]吡啶）的硒化IP对HepG2细胞显示出高细胞毒性（半最大抑制浓度[IC_50]=0.03 mM）和对该肿瘤细胞系的选择性。在无毒浓度下，IP-Se-06降低Bcl-xL蛋白水平，增加p53水平，从而抑制细胞增殖和凋亡。该化合物降低了细胞外信号调节激酶1/2蛋白的水平，并改变了参与细胞周期、肿瘤生长和存活的蛋白质水平（细胞周期蛋白B1，细胞周期蛋白依赖激酶2）。此外，IP-Se-06降低了S期细胞的数量。此外，IP-Se-06导致活性氧生成增加，改变抗氧化防御，并导致DNA断裂。最后，IP-Se-06显著抑制小鼠艾氏腹水肿瘤的生长，延长生存时间，并抑制血管生成。因此，IP-Se-06可能是开发肝癌治疗药物的重要化合物。

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