AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids.

Skarydova, L., Zivna, L., Xiong, G. M., Maser, Edmund and Wsol, V. (2009) AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids. Chemico-Biological Interactions, 178 (1-3). pp. 138-144. DOI 10.1016/j.cbi.2008.10.015.

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Abstract

AKR1C3 (also known as 17 beta-hydroxysteroid dehydrogenase type 5 or 3(x-hydroxysteroid dehydrogenase type 2) functions as a 3-keto, 17-keto and 20-ketosteroid reductase and as a 3 alpha-, 17 beta- and 20 alpha-hydroxysteroid oxidase. Relatively high mRNA expression of AKR1C3 was found in human prostate and mammary gland where it is implicated in regulating ligand access to the androgen and estrogen receptor, respectively. AKR1C3 is an interesting target for the development of agents for treating hormone-dependent forms of cancer like prostate cancer, breast cancer, and endometrial cancer. However, only a few clinically promising and selective inhibitors have been reported so far. Very potent inhibitors of AKR1C3 are the non-steroidal anti-inflammatory drugs, e.g. indomethacin or flufenamic acid. Also dietary phytoestrogens such as coumestrol, quercetin, and biochanin were reported to inhibit the enzyme in low micromolar concentrations. In this study, some dietary flavonoids and other phenolic compounds were tested for their ability to specifically inhibit AKR1C3. Carbonyl reduction of the anticancer drug oracin, which is a very good substrate for AKR1C3 and which could be well monitored by a sensitive HPLC system with fluorescence detection, was employed to determine the inhibitory potency of the compounds. Our results reveal that AKR1C3 could be potentially un-competitively inhibited by 2'-hydroxyflavanone, whose IC50 value of 300 nM is clinically promising. Moreover, since the inhibition is selective towards AKR1C3, 2'-hydroxyflavanone could be useful for treating or preventing hormone-dependent malignancies like prostate and breast cancer. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

Document Type: Article
Keywords: aldo-keto reductases (akrs)flavonoids oracin inhibition selective inhibitor keto reductase superfamily prostaglandin-f synthase steroid-hormone action hydroxysteroid dehydrogenases carbonyl reductases plasma type-5 1c3 phytoestrogens inactivation
Research affiliation: Kiel University
OceanRep > The Future Ocean - Cluster of Excellence
Refereed: Yes
Open Access Journal?: No
Publisher: Elsevier
Projects: Future Ocean
Date Deposited: 11 Feb 2011 12:15
Last Modified: 23 Sep 2019 20:55
URI: https://oceanrep.geomar.de/id/eprint/9742

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