Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea; Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea.
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Seoul, 02447, Republic of Korea.
Food Chem Toxicol. 2019 Feb;124:101-111. doi: 10.1016/j.fct.2018.11.062. Epub 2018 Nov 30.
In this study, several resveratrol analogs were synthesized and evaluated in search of a more effective anti-proliferative resveratrol analog. Among the evaluated resveratrol analogs, we have identified N-(4-methoxyphenyl)-3,5-dimethoxybenamide (MPDB) as a potent anti-proliferative compound. Treatment with MPDB resulted in G/M phase cell cycle arrest, which was accompanied by alteration of G/M-related protein expression and phosphorylation. MPDB-induced G/M arrest was blocked by transfection of ATM/ATR siRNAs, indicating the critical role of ATM/ATR in G/M phase arrest. In addition, treatment with MPDB displayed the activation of caspase and decreased Bcl-xl protein expression after 20 h in HeLa cells. Moreover, MPDB increased cytosolic cytochrome c release and Fas and Fas-L protein expression, indicating intrinsic and extrinsic apoptosis pathway, respectively. These results suggest that MPDB is a new and potent compound that induces ATM/ATR-dependent G/M phase cell cycle arrest and apoptosis, implicating it as a putative candidate in the investment of cervical cancer therapy.
在这项研究中，我们合成了几种白藜芦醇类似物，并对其进行了评估，以期寻找更有效的抗增殖白藜芦醇类似物。在所评估的白藜芦醇类似物中，我们已确定 N-(4-甲氧基苯基)-3,5-二甲氧基苯甲酰胺 (MPDB) 是一种有效的抗增殖化合物。用 MPDB 处理会导致 G/M 期细胞周期停滞，这伴随着 G/M 相关蛋白表达和磷酸化的改变。用 ATM/ATR siRNA 转染可阻断 MPDB 诱导的 G/M 期阻滞，表明 ATM/ATR 在 G/M 期阻滞中起关键作用。此外，在 HeLa 细胞中，用 MPDB 处理 20 小时后会显示 caspase 的激活和 Bcl-xl 蛋白表达的降低。此外，MPDB 增加了细胞质细胞色素 c 的释放以及 Fas 和 Fas-L 蛋白的表达，分别表明内在和外在的细胞凋亡途径。这些结果表明，MPDB 是一种诱导 ATM/ATR 依赖性 G/M 期细胞周期停滞和细胞凋亡的新型有效化合物，表明它可能成为宫颈癌治疗的候选药物。
