Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.

Article Details

Citation

Endo S, Matsunaga T, Kanamori A, Otsuji Y, Nagai H, Sundaram K, El-Kabbani O, Toyooka N, Ohta S, Hara A

Selective inhibition of human type-5 17beta-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.

J Nat Prod. 2012 Apr 27;75(4):716-21. doi: 10.1021/np201002x. Epub 2012 Apr 16.

PubMed ID
22506594 [ View in PubMed
]
Abstract

The human aldo-keto reductase (AKR) 1C3, also known as type-5 17beta-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 muM with an IC(50) value of about 30 muM. 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
3-carboxamido-1,3,5(10)-estratrien-17(R)-spiro-2'(5',5'-dimethyl-6'oxo)tetrahydropyranAldo-keto reductase family 1 member C3Ki (nM)6.9N/AN/ADetails
IndomethacinAldo-keto reductase family 1 member C3IC 50 (nM)4100N/AN/ADetails