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.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan. sendo@gifu-pu.ac.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Ayano
authors.initials: A
authors.lastname: Kanamori
authors.forename: Yoko
authors.initials: Y
authors.lastname: Otsuji
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagai
authors.forename: Krithika
authors.initials: K
authors.lastname: Sundaram
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Naoki
authors.initials: N
authors.lastname: Toyooka
authors.forename: Shozo
authors.initials: S
authors.lastname: Ohta
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000074425:Aldo-Keto Reductase Family 1 Member C3; D001938:Brazil; D018360:Crystallography, X-Ray; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors*; D008297:Male; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011429:Propolis / Q000737:chemistry*; D013237:Stereoisomerism; D014255:Trichothecenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014255:Trichothecenes; D011429:Propolis; C012764:baccharin; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C031051:prostaglandin-F synthase; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3