Inhibition of Human Aldose Reductase-Like Protein (AKR1B10) by α- and γ-Mangostins, Major Components of Pericarps of Mangosteen

Abstract

A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently identified as both diagnostic marker and therapeutic target in the treatment of several types of cancer. In this study, we have examined AKR1B10 inhibition by five xanthone derivatives, components of pericarps of mangosteen, of which α-and γ-mangostins show potential anti-cancer properties. Among the five xanthones, γ-mangostin was found to be the most potent competitive inhibitor (inhibition constant, 5.6 nM), but its 7-methoxy derivative, α-mangostin, was the second potent inhibitor (inhibition constant, 80 nM). Molecular docking of the two mangostins in AKR1B10 and site-directed mutagenesis of the putative binding residues revealed that Phe123, Trp220, Val301 and Gln303 are important for the tight binding of γ-mangostin, and suggested that the 7-methoxy group of α-mangostin impairs the inhibitory potency by altering the orientation of the inhibitor molecule in the substrate-binding site of the enzyme.Key words aldo-keto reductase 1B10; aldose reductase; mangostin; xanthone; anti-cancer property; molecular docking A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, is a reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reductase, which was originally identified as a human aldose reductase (AKR1B1)-like protein that is up-regulated in hepatocellular carcinomas. 1)Over-expression of AKR1B10 has been also observed in other tumors, such as smokers' non-small cell lung carcinomas, 2) uterine carcinomas, 3) cholangiocarcinomas, 4) pancreatic carcinoma, 5) and breast cancer.6) The silencing of the AKR1B10 gene results in growth inhibition of cancer cells [5][6][7][8] and hepatocellular carcinoma xenografts in mice, 9) and its elevated expression in turn promotes proliferation of cancer cells, 10,11) indicating that the enzyme participates in tumor development. Due to its high catalytic efficiency towards aliphatic aldehydes, retinals and isoprenyl aldehydes, 1,[6][7][8]12,13) the roles suggested for AKR1B10 in cell carcinogenesis and tumor development are detoxification of cytotoxic carbonyls derived from lipid peroxidation, [6][7][8] decrease in retinoic acid synthesis, 12) and modulation of protein prenylation. 6,11,13) In addition, AKR1B10 is suggested to promote fatty acid synthesis in liver cancer cells by blocking the ubiquitin-dependent degradation of acetyl CoA carboxylase. 8) Thus, this enzyme has been recognized not only as a potential diagnostic and/or prognostic marker, but also as a potential therapeutic target for the prevention and treatment of the above types of cancer. However, because of the high structural similarity between AKR1B10 and AKR1B1 that plays distinct roles in glucose and prostaglandin metabolism, 14,15) the selective inhibition of AKR1B10 over AKR1B1 is required for the development of treatments targeting the types of cancer linked to AKR1B10.Synthetic and natural compounds that show inhibitory effects on AKR1B10 have been reported, as reviewed by Matsunaga et al. 1...

Inhibitor selectivity between aldo–keto reductase superfamily members AKR1B10 and AKR1B1: Role of Trp112 (Trp111)

“…However, the strong activities toward AKR1B10 and AKR1B1, but weak activity toward AKR1A1 of chromene‐3‐carboxamide derivatives [27], suggest that this type of compound triggers the “specificity pocket” opening and Trp112 flip to give an “AKR1B1‐like” active site in AKR1B10. Furthermore, the apparent tendency of compounds such as γ‐mangostin [29], curcumin [13], and 5α‐pregnane‐21‐ol‐3, 20‐dione [28] to selectively inhibit AKR1B10 indicates that the increased accessibility of the anionic site of AKR1B10 is essential for their selectivity. To support this mechanism, we prepared the AKR1B10 Gln114Thr/Ser304Cys double mutant.…”

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

“…-and -mangostins, are xanthone derivatives, constituents of the pericarp of mangosteen. Both of them showed an inhibitory effect on AKR1B10 in a competitive manner, and -mangostin (21) was the more potent one [34]. The putative binding model revealed that the high inhibition performance by -mangostin was due to its tight binding, which was mainly provided by Gln-303, Val-301, Phe-123 and Trp-220.…”

“…The development of potent and selective AKR1B10 inhibitor as anticancer drugs has attracted growing attentions. Recently, many AKR1B10 inhibitors have been developed rapidly [24][25][26][27][28][29][30][31][32][33][34][35][36][37]. We here, review the recent publications and patents related to AKR1B10 inhibitors.…”

Aldo-Keto Reductase Family 1 Member B10 Inhibitors: Potential Drugs for Cancer Treatment

“…Subsequently, in vitro studies have discovered potent and selective AKR1B10 inhibitors [24, 26-29, 33, 34, 38]. The analysis of interactions between AKR1B10 and tolrestat shows that residues Tyr-49, His-111, and Trp-112 form hydrogen bonds with the carboxyl group in tolrestat, together with the positive charge of cofactor, defining an anion-binding pocket.…”

“…α- and γ-mangostins, are xanthone derivatives, constituents of the pericarp of mangosteen. Both of them showed an inhibitory effect on AKR1B10 in a competitive manner, and γ-mangostin ( 21 ) was the more potent one [34]. The putative binding model revealed that the high inhibition performance by γ-mangostin was due to its tight binding, which was mainly provided by Gln-303, Val-301, Phe-123 and Trp-220.…”