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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
Journal of Biochemical and Molecular Toxicology ( IF 3.2 ) Pub Date : 2020-10-30 , DOI: 10.1002/jbt.22663 Daniela Coelho Dos Santos 1 , Jamal Rafique 2 , Sumbal Saba 3 , Gabriela M Almeida 1 , Tâmila Siminski 1 , Cynthia Pádua 1 , Danilo W Filho 4 , Ariane Zamoner 5 , Antonio L Braga 6 , Rozangela C Pedrosa 1 , Fabiana Ourique 1, 5
Journal of Biochemical and Molecular Toxicology ( IF 3.2 ) Pub Date : 2020-10-30 , DOI: 10.1002/jbt.22663 Daniela Coelho Dos Santos 1 , Jamal Rafique 2 , Sumbal Saba 3 , Gabriela M Almeida 1 , Tâmila Siminski 1 , Cynthia Pádua 1 , Danilo W Filho 4 , Ariane Zamoner 5 , Antonio L Braga 6 , Rozangela C Pedrosa 1 , Fabiana Ourique 1, 5
Affiliation
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Imidazo[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 [IC50] = 0.03 µM) 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.
中文翻译：
硒化咪唑并[1,2-a]吡啶对肝细胞癌HepG2细胞和体内凋亡的氧化损伤介导和抗增殖作用
咪唑并[1,2- a ]吡啶（IP）和有机硒化合物因其药理活性而被广泛用于药物化学中。肝细胞癌（HCC）的治疗选择很少，不幸的是，预后很差。因此，迫切需要开发新的治疗药物。本研究旨在评估硒化IP对HepG2细胞和体内的抗肿瘤机制。硒化IP称为IP-Se-06（3-（（（2-甲氧基苯基）硒基）-7-甲基-2-苯基咪唑[1,2- a ]吡啶））对HepG2细胞显示出高细胞毒性（半数最大抑制浓度[ IC 50 ] = 0.03 µM）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的蛋白质水平并增加p53的水平，从而导致细胞增殖和凋亡的抑制。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水平（cyclin B1，cyclin依赖性激酶2）。此外，IP-Se-06减少了S阶段的单元数。此外，IP-Se-06导致活性氧种类的产生增加，抗氧化剂防御机制的改变以及导致DNA片段化。最后，IP-Se-06显着抑制了小鼠艾氏腹水肿瘤的生长，延长了生存时间，并抑制了血管生成。因此，IP-Se-06 可能是有关开发用于HCC治疗的治疗药物的重要化合物。
更新日期：2020-10-30
中文翻译：
硒化咪唑并[1,2-a]吡啶对肝细胞癌HepG2细胞和体内凋亡的氧化损伤介导和抗增殖作用
咪唑并[1,2- a ]吡啶（IP）和有机硒化合物因其药理活性而被广泛用于药物化学中。肝细胞癌（HCC）的治疗选择很少，不幸的是，预后很差。因此，迫切需要开发新的治疗药物。本研究旨在评估硒化IP对HepG2细胞和体内的抗肿瘤机制。硒化IP称为IP-Se-06（3-（（（2-甲氧基苯基）硒基）-7-甲基-2-苯基咪唑[1,2- a ]吡啶））对HepG2细胞显示出高细胞毒性（半数最大抑制浓度[ IC 50 ] = 0.03 µM）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的蛋白质水平并增加p53的水平，从而导致细胞增殖和凋亡的抑制。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水平（cyclin B1，cyclin依赖性激酶2）。此外，IP-Se-06减少了S阶段的单元数。此外，IP-Se-06导致活性氧种类的产生增加，抗氧化剂防御机制的改变以及导致DNA片段化。最后，IP-Se-06显着抑制了小鼠艾氏腹水肿瘤的生长，延长了生存时间，并抑制了血管生成。因此，IP-Se-06 可能是有关开发用于HCC治疗的治疗药物的重要化合物。
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