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.

• Authors: Satoshi Endo, Toshiyuki Matsunaga, Ayano Kanamori, Yoko Otsuji, Hiroko Nagai, Krithika Sundaram, Ossama El-Kabbani, Naoki Toyooka, Shozo Ohta, Akira Hara
• Journal: Journal of natural products (J Nat Prod) Vol. 75 Issue 4 Pg. 716-21 (Apr 27 2012) ISSN: 1520-6025 [Electronic] United States
• PMID: 22506594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 American Chemical Society and American Society of Pharmacognosy

Chemical References

• Trichothecenes
• Propolis
• baccharin
• 3-Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• prostaglandin-F synthase
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3

Topics

• 3-Hydroxysteroid Dehydrogenases (antagonists & inhibitors)
• Aldo-Keto Reductase Family 1 Member C3
• Brazil
• Crystallography, X-Ray
• Humans
• Hydroxyprostaglandin Dehydrogenases (antagonists & inhibitors)
• Male
• Molecular Conformation
• Nuclear Magnetic Resonance, Biomolecular
• Propolis (chemistry)
• Stereoisomerism
• Trichothecenes (chemistry, pharmacology)