Selective inhibition of human type-5 17β-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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Trichothecenes / pharmacology*


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