Satoshi Endo,*,† Toshiyuki Matsunaga,† Ayano Kanamori,† Yoko Otsuji,† Hiroko Nagai,† Krithika Sundaram,‡ Ossama El-Kabbani,‡ Naoki Toyooka,§,⊥ Shozo Ohta,∥ and Akira Hara†
†Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan
‡Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
§Graduate School of Science and Technology for Research and ⊥Graduate School of Innovative Life Science, University of Toyama, Toyama 930-8555, Japan
∥Nagaragawa Research Center, API Co., Ltd., Gifu 502-0071, Japan
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 (Ki 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 non- conserved 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 IC50 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.
* THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FOOD AND DRUG ADMINISTRATION. THIS IS NOT INTENDED TO DIAGNOSE, TREAT CURE OR PREVENT ANY DISEASE.