Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
J Nat Prod. 2012 Apr 27;75(4):716-21. doi: 10.1021/np201002x. Epub 2012 Apr 16.
The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.
人醛酮还原酶 1C3（aldo-keto reductase 1C3，AKR1C3），也被称为 17β-羟甾类脱氢酶 5 型和前列腺素 F 合酶，被认为是治疗前列腺癌和乳腺癌的一种有潜力的治疗靶点。在这项研究中，采用具有潜在抗肿瘤活性的巴西蜂胶衍生肉桂酸衍生物来研究 AKR1C3 的抑制情况，结果发现巴卡丁 III（baccharin III，1）是一种强效的竞争性抑制剂（K(i) 为 56 nM），具有很高的选择性，对其他 AKR1C 同工酶（AKR1C1、AKR1C2 和 AKR1C4）没有明显的抑制作用。分子对接和定点突变研究表明，AKR1C3 中的非保守残基丝氨酸 118、蛋氨酸 120 和苯丙氨酸 311 对于确定 1 的抑制效力和选择性非常重要。1 抑制了 AKR1C3 介导的癌细胞中 17-酮甾类和法呢基醛的代谢，其有效浓度为 0.2 μM，IC50 值约为 30 μM。此外，1 抑制了 AKR1C3 过表达刺激的 PC3 前列腺癌细胞的增殖。这项研究首次证明 1 是 AKR1C3 的一种高选择性抑制剂。
