Zemanova Lucie, Hofman Jakub, Novotna Eva, Musilek Kamil, Lundova Tereza, Havrankova Jana, Hostalkova Anna, Chlebek Jakub, Cahlikova Lucie, Wsol Vladimír
Department of Chemistry, Faculty of Science, University of Hradec Kralove , Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic.
J Nat Prod. 2015 Nov 25;78(11):2666-74. doi: 10.1021/acs.jnatprod.5b00616. Epub 2015 Nov 3.
AKR1B10 is an NADPH-dependent reductase that plays an important function in several physiological reactions such as the conversion of retinal to retinol, reduction of isoprenyl aldehydes, and biotransformation of procarcinogens and drugs. A growing body of evidence points to the important role of the enzyme in the development of several types of cancer (e.g., breast, hepatocellular), in which it is highly overexpressed. AKR1B10 is regarded as a therapeutic target for the treatment of these diseases, and potent and specific inhibitors may be promising therapeutic agents. Several inhibitors of AKR1B10 have been described, but the area of natural plant products has been investigated sparingly. In the present study almost 40 diverse phenolic compounds and alkaloids were examined for their ability to inhibit the recombinant AKR1B10 enzyme. The most potent inhibitors-apigenin, luteolin, and 7-hydroxyflavone-were further characterized in terms of IC50, selectivity, and mode of action. Molecular docking studies were also conducted, which identified putative binding residues important for the interaction. In addition, cellular studies demonstrated a significant inhibition of the AKR1B10-mediated reduction of daunorubicin in intact cells by these inhibitors without a considerable cytotoxic effect. Although these compounds are moderately potent and selective inhibitors of AKR1B10, they constitute a new structural type of AKR1B10 inhibitor and may serve as a template for the development of better inhibitors.
醛酮还原酶1B10（AKR1B10）是一种依赖烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的还原酶，在多种生理反应中发挥重要作用，如视网膜向视黄醇的转化、异戊烯醛的还原以及前致癌物和药物的生物转化。越来越多的证据表明，该酶在几种类型癌症（如乳腺癌、肝细胞癌）的发展中起着重要作用，在这些癌症中它高度过表达。AKR1B10被视为治疗这些疾病的靶点，强效且特异性的抑制剂可能是有前景的治疗药物。已经描述了几种AKR1B10的抑制剂，但天然植物产物领域的研究较少。在本研究中，检测了近四十种不同的酚类化合物和生物碱抑制重组AKR1B10酶的能力。对最有效的抑制剂——芹菜素、木犀草素和7-羟基黄酮——进一步进行了半数抑制浓度（IC50）、选择性和作用模式方面的表征。还进行了分子对接研究，确定了对相互作用重要的推定结合残基。此外，细胞研究表明，这些抑制剂在完整细胞中能显著抑制AKR1B10介导的柔红霉素还原，且没有相当大的细胞毒性作用。尽管这些化合物是中等效力和选择性的AKR1B10抑制剂，但它们构成了一种新的AKR1B10抑制剂结构类型，可能作为开发更好抑制剂的模板。
