title: Selective inhibition of the tumor marker aldo-keto reductase family member 1B10 by oleanolic acid.
abstract: A human member of the aldo-keto reductase (AKR) superfamily, AKR1B10, was recently suggested as a therapeutic target in the treatment of several types of cancer. Due to its high sequence identity with human aldose reductase (AKR1B1), selective inhibition of AKR1B10 compared with AKR1B1 is required for the development of anticancer agents. In this study, we have examined AKR1B10 inhibition by seven pentacyclic triterpenes (1-7) that show potential anticancer properties. Among them, oleanolic acid (1) was found to be the most potent competitive inhibitor (inhibition constant, 72 nM) with the highest AKR1B10/AKR1B1 selectivity ratio of 1370. Molecular docking of 1 with AKR1B10 and AKR1B1 and site-directed mutagenesis studies suggested that the nonconserved residues Val301 and Gln303 in AKR1B10 are important for determining its inhibitory potency and selectivity. Oleanolic acid (1) also inhibited the cellular metabolism by AKR1B10 (IC(50), 4 μM) and decreased mitomycin C tolerance of colon cancer HT29 cells. Thus, the selective and potent inhibition of AKR1B10 by 1 may be related to a possible cancer inhibitory role.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: Mayuko
authors.initials: M
authors.lastname: Takemura
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Midori
authors.initials: M
authors.lastname: Soda
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhao
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tajima
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000235:genetics; D000074408:Aldo-Keto Reductases; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000187:drug effects; D009828:Oleanolic Acid / Q000737:chemistry / Q000494:pharmacology*; D053978:Pentacyclic Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D053978:Pentacyclic Triterpenes; D016685:Mitomycin; D009828:Oleanolic Acid; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase