PT  - JOURNAL ARTICLE
AU  - Zhi-Xing Cao
AU  - Yi Wen
AU  - Jun-Lin He
AU  - Shen-Zhen Huang
AU  - Fei Gao
AU  - Chuan-Jie Guo
AU  - Qing-Qing Liu
AU  - Shu-Wen Zheng
AU  - Dao-Yin Gong
AU  - Yu-Zhi Li
AU  - Ruo-Qi Zhang
AU  - Jian-Ping Chen
AU  - Cheng Peng
TI  - Isoliquiritigenin, an orally available natural FLT3 inhibitor from licorice, exhibits selective anti-AML efficacy in vitro and in vivo
AID  - 10.1124/mol.119.116129
DP  - 2019 Jan 01
TA  - Molecular Pharmacology
PG  - mol.119.116129
4099  - http://molpharm.aspetjournals.org/content/early/2019/08/28/mol.119.116129.short
4100  - http://molpharm.aspetjournals.org/content/early/2019/08/28/mol.119.116129.full
AB  - Licorice is a medicinal herb widely used to treat inflammation-related diseases in china. Isoliquiritigenin (ISL) is an important constituent of Licorice, and possesses multiple bioactivitys. In this study, we examined the selective anti-AML (Acute myeloid leukemia) property of ISL via targeting FLT3, a certified valid target for the treatment of AML. In vitro, ISL potently inhibited FLT3 kinase with an IC50 of 115.1 ± 4.2 nM, selectively inhibited the viability of FLT3-ITD or FLT3-ITD/F691L mutant AML cells, and showed very weak activity towards other tested cell lines or kinases.Western blotting detection revealed that ISL potently inhibited the activation of FLT3/Erk1/2/STAT5 signal in AML cells. Meanwhile, Molecular docking study indicated that ISL could stably form aromatic interactions and hydrogen bonds within the kinase domain of FLT3. In vivo, oral administration of ISL significantly inhibited the MV4-11 tumor growth and prolonged the survival time of bone marrow engraftment AML mice via decreasing the expression of Ki67, and induced apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor to be a promising novel potential natural bioactive compound for the treatment of AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might posess potential therapeutic effects in the treatment of AML, and combining with other drugs maight provide more effective treatment strategy.SIGNIFICANCE STATEMENT Isoliquiritigenin selectively inhibited the viability of FLT3-ITD mutant AML cells via targeting FLT3 Oral administration of Isoliquiritigenin could significantly inhibit in vivo tumor growth of AML cells in xenograft tumor model and bone marrow model with well tolerance. Isoliquiritigenin is an orally available natural FLT3 inhibitor from licorice. Isoliquiritigenin still retained a good inhibitory activity against FLT3-ITD/F691L mutation, a resistance kinase domain mutation against sorafenib and AC220