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Article: Isoliquiritigenin, an orally available natural FLT3 inhibitor from licorice, exhibits selective anti-Acute Myeloid Leukemia efficacy in vitro and in vivo

TitleIsoliquiritigenin, an orally available natural FLT3 inhibitor from licorice, exhibits selective anti-Acute Myeloid Leukemia efficacy in vitro and in vivo
Authors
KeywordsLeukemia
Myeloid
Acute
Mutation
Internal tandem
Issue Date2019
PublisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org
Citation
Molecular Pharmacology, 2019, v. 96 n. 5, p. 589-599 How to Cite?
AbstractLicorice is a medicinal herb widely used to treat inflammation-related diseases in China. Isoliquiritigenin (ISL) is an important constituent of licorice and possesses multiple bioactivities. In this study, we examined the selective anti-AML (acute myeloid leukemia) property of ISL via targeting FMS-like tyrosine kinase-3 (FLT3), a certified valid target for treating AML. In vitro, ISL potently inhibited FLT3 kinase, with an IC50 value of 115.1 ± 4.2 nM, and selectively inhibited the proliferation of FLT3–internal tandem duplication (FLT3-ITD) or FLT3-ITD/F691L mutant AML cells. Moreover, it showed very weak activity toward other tested cell lines or kinases. Western blot immunoassay revealed that ISL significantly inhibited the activation of FLT3/Erk1/2/signal transducer and activator of transcription 5 (STAT5) signal in AML cells. Meanwhile, a 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 flank tumor growth and prolonged survival in the bone marrow transplant model via decreasing the expression of Ki67 and inducing apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor. ISL could also be a potential natural bioactive compound for treating AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might possess potential therapeutic effects for treating AML, providing a new strategy for anti-AML.
Persistent Identifierhttp://hdl.handle.net/10722/277136
ISSN
2017 Impact Factor: 3.978
2015 SCImago Journal Rankings: 2.047

 

DC FieldValueLanguage
dc.contributor.authorCao, ZX-
dc.contributor.authorWEN, Y-
dc.contributor.authorHE, JL-
dc.contributor.authorHuang, SZ-
dc.contributor.authorGAO, F-
dc.contributor.authorGuo, CJ-
dc.contributor.authorLIU, QQ-
dc.contributor.authorZheng, SW-
dc.contributor.authorGong, DY-
dc.contributor.authorLi, YZ-
dc.contributor.authorZhang, RQ-
dc.contributor.authorChen, JP-
dc.contributor.authorPeng, C-
dc.date.accessioned2019-09-20T08:45:17Z-
dc.date.available2019-09-20T08:45:17Z-
dc.date.issued2019-
dc.identifier.citationMolecular Pharmacology, 2019, v. 96 n. 5, p. 589-599-
dc.identifier.issn0026-895X-
dc.identifier.urihttp://hdl.handle.net/10722/277136-
dc.description.abstractLicorice is a medicinal herb widely used to treat inflammation-related diseases in China. Isoliquiritigenin (ISL) is an important constituent of licorice and possesses multiple bioactivities. In this study, we examined the selective anti-AML (acute myeloid leukemia) property of ISL via targeting FMS-like tyrosine kinase-3 (FLT3), a certified valid target for treating AML. In vitro, ISL potently inhibited FLT3 kinase, with an IC50 value of 115.1 ± 4.2 nM, and selectively inhibited the proliferation of FLT3–internal tandem duplication (FLT3-ITD) or FLT3-ITD/F691L mutant AML cells. Moreover, it showed very weak activity toward other tested cell lines or kinases. Western blot immunoassay revealed that ISL significantly inhibited the activation of FLT3/Erk1/2/signal transducer and activator of transcription 5 (STAT5) signal in AML cells. Meanwhile, a 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 flank tumor growth and prolonged survival in the bone marrow transplant model via decreasing the expression of Ki67 and inducing apoptosis. Taken together, the present study identified a novel function of ISL as a selective FLT3 inhibitor. ISL could also be a potential natural bioactive compound for treating AML with FLT3-ITD or FLT3-ITD/F691L mutations. Thus, ISL and licorice might possess potential therapeutic effects for treating AML, providing a new strategy for anti-AML.-
dc.languageeng-
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics. The Journal's web site is located at http://www.molpharm.org-
dc.relation.ispartofMolecular Pharmacology-
dc.subjectLeukemia-
dc.subjectMyeloid-
dc.subjectAcute-
dc.subjectMutation-
dc.subjectInternal tandem-
dc.titleIsoliquiritigenin, an orally available natural FLT3 inhibitor from licorice, exhibits selective anti-Acute Myeloid Leukemia efficacy in vitro and in vivo-
dc.typeArticle-
dc.identifier.emailChen, JP: abchen@hkucc.hku.hk-
dc.identifier.authorityChen, JP=rp01316-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1124/mol.119.116129-
dc.identifier.pmid31462456-
dc.identifier.scopuseid_2-s2.0-85072849330-
dc.identifier.hkuros305453-
dc.identifier.volume96-
dc.identifier.issue5-
dc.identifier.spage589-
dc.identifier.epage599-
dc.publisher.placeUnited States-

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