TY - JOUR
T1 - Selective inhibition of the tumor marker aldo-keto reductase family member 1B10 by oleanolic acid
AU - Takemura, Mayuko
AU - Endo, Satoshi
AU - Matsunaga, Toshiyuki
AU - Soda, Midori
AU - Zhao, Hai-Tao
AU - El-Kabbani, Ossama
AU - Tajima, Kazuo
AU - Iinuma, Munekazu
AU - Hara, Akira
PY - 2011
Y1 - 2011
N2 - A human member of the aldo-keto reductase (AICR) 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 (AICR1B1), 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 pentacydic 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/A1CR1B1 selectivity ratio of 1370. Molecular docking of 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 mu M) 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.
AB - A human member of the aldo-keto reductase (AICR) 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 (AICR1B1), 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 pentacydic 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/A1CR1B1 selectivity ratio of 1370. Molecular docking of 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 mu M) 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.
UR - http://pubs.acs.org.ezproxy.lib.monash.edu.au/doi/full/10.1021/np200118q
U2 - 10.1021/np200118q
DO - 10.1021/np200118q
M3 - Article
SN - 0163-3864
VL - 74
SP - 1201
EP - 1206
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 5
ER -
