Graduate School of Pharmaceutical Sciences, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
School of Pharmacy, Kitasato University 5-9-1 Shirokane, Minato-ku, Tokyo, 108-8641, Japan.
Pharmacol Res Perspect. 2015 Mar;3(2):e00121. doi: 10.1002/prp2.121. Epub 2015 Feb 10.
Cordycepin, which is an analogue of a nucleoside adenosine, exhibits a wide variety of pharmacological activities including anticancer effects. In this study, ADA1- and ADA2-expressing HEK293 cells were established to determine the major ADA isoform responsible for the deamination of cordycepin. While the metabolic rate of cordycepin deamination was similar between ADA2-expressing and Mock cells, extensive metabolism of cordycepin was observed in the ADA1-expressing cells with K m and V max values of 54.9 μmol/L and 45.8 nmole/min/mg protein. Among five natural substances tested in this study (kaempferol, quercetin, myricetin, naringenin, and naringin), naringin strongly inhibited the deamination of cordycepin with K i values of 58.8 μmol/L in mouse erythrocytes and 168.3 μmol/L in human erythrocytes. A treatment of Jurkat cells with a combination of cordycepin and naringin showed significant cytotoxicity. Our in silico study suggests that not only small molecules such as adenosine derivatives but also bulky molecules like naringin can be a potent ADA1 inhibitor for the clinical usage.
蛹虫草素是一种核苷腺苷类似物，具有广泛的药理活性，包括抗癌作用。在这项研究中，建立了表达 ADA1 和 ADA2 的 HEK293 细胞，以确定负责蛹虫草素脱氨作用的主要 ADA 同工酶。虽然 ADA2 表达细胞和 Mock 细胞中蛹虫草素脱氨的代谢率相似，但在 ADA1 表达细胞中观察到蛹虫草素的广泛代谢，其 K m 和 V max 值分别为 54.9 μmol/L 和 45.8 nmol/min/mg 蛋白。在本研究中测试的五种天然物质（山柰酚、槲皮素、杨梅素、柚皮苷和新橙皮苷）中，柚皮苷强烈抑制蛹虫草素的脱氨作用，在小鼠红细胞中的 K i 值为 58.8 μmol/L，在人红细胞中的 K i 值为 168.3 μmol/L。蛹虫草素和柚皮苷联合处理 Jurkat 细胞显示出显著的细胞毒性。我们的计算机模拟研究表明，不仅是像腺苷衍生物这样的小分子，而且是像柚皮苷这样的大分子量分子，也可以成为临床应用中有效的 ADA1 抑制剂。
