Uesawa Yoshihiro, Sakagami Hiroshi, Okudaira Noriyuki, Toda Kazuhiro, Takao Koichi, Kagaya Hajime, Sugita Yoshiaki
Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Tokyo, Japan
Meikai University Research Institute of Odontology (M-RIO), Mekai University School of Dentistry, Tokyo, Japan.
Anticancer Res. 2018 Feb;38(2):817-823. doi: 10.21873/anticanres.12289.
BACKGROUND/AIM: Many phenolic acid phenethyl esters possess diverse biological effects including antioxidant, cytoprotective, anti-inflammation and anti-tumor activities. However, most previous antitumor studies have not considered the cytotoxicity against normal cells. Ten cinnamic acid phenetyl esters were subjected to quantitative structure-activity relationship (QSAR) analysis, based on their cytotoxicity and tumor-specificity, in order to find their new biological activities.
Cytotoxicity against four human oral squamous cell carcinoma cell lines and three oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC) against normal oral cells to that against human oral squamous cell carcinoma cell lines. Potency-selectivity expression (PSE) value was calculated by dividing the TS value by CC against tumor cells. Apoptosis markers were detected by western blot analysis. Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by force-field minimization.
Western blot analysis demonstrated that [] stimulated the cleavage of caspase-3, suggesting the induction of apoptosis. QSAR analysis demonstrated that TS values were correlated with shape, size and ionization potential.
Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drugs.
背景/目的：许多酚酸苯乙酯具有多种生物学效应，包括抗氧化、细胞保护、抗炎和抗肿瘤活性。然而，以往大多数抗肿瘤研究并未考虑对正常细胞的细胞毒性。基于十种肉桂酸苯乙酯的细胞毒性和肿瘤特异性，对其进行定量构效关系（QSAR）分析，以发现它们的新生物活性。
采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）法测定对四种人口腔鳞状细胞癌细胞系和三种口腔正常间充质细胞的细胞毒性。通过平均50%细胞毒性浓度（CC）对正常口腔细胞与对人口腔鳞状细胞癌细胞系的比值评估肿瘤特异性（TS）。通过将TS值除以对肿瘤细胞测定的CC来计算效价-选择性表达（PSE）值。通过蛋白质印迹分析检测凋亡标志物。基于通过力场最小化优化的构象计算物理化学、结构和量子化学参数。
蛋白质印迹分析表明[ ]刺激了半胱天冬酶-3的切割，提示诱导了凋亡。QSAR分析表明TS值与形状、大小和电离势相关。
先导化合物的化学修饰可能是设计新型抗癌药物的潜在选择。
