Inhibition of AKR1C3-mediated [14C]farnesal metabolism in human MCF7 cells incubated for 2 hrs prior to substrate addition measured after 6 hrs
- Deposit:2013-05-16
- Modify:2022-08-30
Title: Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.
Abstract: 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.
Journal: J Nat Prod
Year: 2012
Volume: 75
Issue: 4
First Page: 716
Last Page: 721
DOI: 10.1021/np201002x
Target ChEMBL ID: CHEMBL4681
ChEMBL Target Name: Aldo-keto-reductase family 1 member C3
ChEMBL Target Type: SINGLE PROTEIN - Target is a single protein chain
Relationship Type: D - Direct protein target assigned
Confidence: Direct single protein target assigned
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