Homoharringtonine synergizes with quizartinib in FLT3-ITD acute myeloid leukemia by targeting FLT3-AKT-c-Myc pathway.
Biochem Pharmacol
; 188: 114538, 2021 06.
Article
in En
| MEDLINE
| ID: mdl-33831397
ABSTRACT
Acute myeloid leukemia (AML) with FLT3 internal tandem duplication (FLT3-ITD) has a dismal prognosis. FLT3 inhibitors have been developed to treat patients with FLT3-ITD AML; however, when used alone, their efficacy is insufficient. FLT3 inhibitors combined with chemotherapy may be a promising treatment for FLT3-ITD AML. Homoharringtonine (HHT) is a classical anti-leukaemia drug with high sensitivity to FLT3-ITD AML cells. Here, we showed that HHT synergizes with a selective next-generation FLT3 inhibitor, quizartinib, to inhibit cell growth/viability and induce cell-cycle arrest and apoptosis in FLT3-ITD AML cells in vitro, significantly inhibit acute myeloid leukemia progression in vivo, and substantially prolong survival of mice-bearing human FLT3-ITD AML. Mechanistically, HHT and quizartinib cooperatively inhibit FLT3-AKT and its downstream targets GSK3ß, c-Myc, and cyclin D1, cooperatively up-regulate the pro-apoptosis proteins Bim and Bax, and down-regulate the anti-apoptosis protein Mcl1. Most strikingly, HHT and quizartinib cooperatively reduce the numbers of side-population (SP) and aldehyde dehydrogenase (ALDH)-positive cells, which reportedly are rich in LSCs. In conclusion, HHT combined with quizartinib may be a promising treatment strategy for patients with FLT3-ITD AML.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Phenylurea Compounds
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Leukemia, Myeloid, Acute
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Proto-Oncogene Proteins c-myc
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Benzothiazoles
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Proto-Oncogene Proteins c-akt
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Fms-Like Tyrosine Kinase 3
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Homoharringtonine
Limits:
Adolescent
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Adult
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Aged80
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Animals
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Female
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Humans
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Male
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Middle aged
Language:
En
Year:
2021
Type:
Article