Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
J Nat Prod. 2011 May 27;74(5):1201-6. doi: 10.1021/np200118q. Epub 2011 May 11.
A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently suggested as a therapeutic target in the treatment of several types of cancer. Due to its high sequence identity with human aldose reductase (AKR1B1), selective inhibition of AKR1B10 compared with AKR1B1 is required for the development of anticancer agents. In this study, we have examined AKR1B10 inhibition by seven pentacyclic triterpenes (1-7) that show potential anticancer properties. Among them, oleanolic acid (1) was found to be the most potent competitive inhibitor (inhibition constant, 72 nM) with the highest AKR1B10/AKR1B1 selectivity ratio of 1370. Molecular docking of 1 with AKR1B10 and AKR1B1 and site-directed mutagenesis studies suggested that the nonconserved residues Val301 and Gln303 in AKR1B10 are important for determining its inhibitory potency and selectivity. Oleanolic acid (1) also inhibited the cellular metabolism by AKR1B10 (IC(50), 4 μM) and decreased mitomycin C tolerance of colon cancer HT29 cells. Thus, the selective and potent inhibition of AKR1B10 by 1 may be related to a possible cancer inhibitory role.
醛酮还原酶 (AKR) 超家族的一个人类成员，AKR1B10，最近被提议作为治疗几种类型癌症的治疗靶点。由于其与人类醛糖还原酶 (AKR1B1) 的高度序列同一性，因此需要选择性抑制 AKR1B10 而不是 AKR1B1，才能开发出抗癌药物。在这项研究中，我们研究了七种具有潜在抗癌特性的五环三萜（1-7）对 AKR1B10 的抑制作用。其中，齐墩果酸（1）被发现是最有效的竞争性抑制剂（抑制常数为 72 nM），对 AKR1B10/AKR1B1 的选择性比为 1370。1 与 AKR1B10 和 AKR1B1 的分子对接以及定点突变研究表明，AKR1B10 中的非保守残基 Val301 和 Gln303 对于确定其抑制效力和选择性很重要。齐墩果酸（1）还抑制 AKR1B10 介导的细胞代谢（IC50，4 μM），并降低结肠癌 HT29 细胞对丝裂霉素 C 的耐受性。因此，1 对 AKR1B10 的选择性和强效抑制可能与可能的抗癌作用有关。
