Piceatannol, a natural trans-stilbene compound, inhibits human glyoxalase I.
Human glyoxalase I (GLO I), a rate-limiting enzyme for detoxification of methylglyoxal (MG), a by-product of glycolysis, is known to be a potential therapeutic target for cancer. Here, we searched new scaffolds from natural compounds for designing novel GLO I inhibitors and found trans-stilbene scaffold. We examined the inhibitory abilities to human GLO I of commercially available trans-stilbene compounds. Among them, piceatannol was found to have the most potent inhibitory activity against human GLO I. Piceatannol could inhibit the proliferation of human lung cancer NCI-H522 cells, which are dependent on GLO I for survival, in a dose- and time-dependent manner. In addition, piceatannol more significantly inhibited the proliferation of NCI-H522 cells than that of NCI-H460 cells, which are less dependent on GLO I. Importantly, overexpression of GLO I in NCI-H522 cells resulted in less sensitive to the antiproliferative activity of piceatannol. Taken together, this is the first report demonstrating that piceatannol inhibits GLO I activity and the GLO I-dependent proliferation of cancer cells. Furthermore, we determined a pharmacophore for novel inhibitors of human GLO I by computational simulation analyses of the binding mode of piceatannol to the enzyme hot spot in the active site. We suggest that piceatannol is a possible lead compound for the development of novel GLO I inhibitory anticancer drugs.
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Genome & Drug Research Center, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan. Electronic address: takasawa@rs.noda.tus.ac.jp.
Ryoko
R
Takasawa
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Haruka
H
Akahane
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Hikari
H
Tanaka
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Nami
N
Shimada
Health Science Research Center, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan.
Takayuki
T
Yamamoto
Health Science Research Center, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan.
Hiroko
H
Uchida-Maruki
Health Science Research Center, Morinaga & Co., Ltd., 2-1-1 Shimosueyoshi, Tsurumi-ku, Yokohama 230-8504, Japan.
Masahiko
M
Sai
Institute for Theoretical Medicine, Inc., Tokyo Institute of Technology Yokohama Venture Plaza W101, 4259-3 Nagatsuda, Midori, Yokohama, Kanagawa 226-8510, Japan.
Atsushi
A
Yoshimori
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan; Genome & Drug Research Center, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
Sei-Ichi
SI
Tanuma
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000473:pathology; D013267:Stilbenes / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; D007791:Lactoylglutathione Lyase
Anticancer; Glyoxalase I; Inhibitor; Piceatannol; Stilbenes