Arsenic trioxide and all-trans-retinoic acid selectively exert synergistic cytotoxicity against FLT3-ITD AML cells via co-inhibition of FLT3 signaling pathways.
Wang LN , Tang YL , Zhang YC , Zhang ZH , Liu XJ , Ke ZY , Li Y , Tan HZ , Huang LB , Luo XQ 
Leuk Lymphoma.2017 Mar 09 ; ():1-13.
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FLT3-ITD mutations occur in approximately 30% of acute myeloid leukemia (AML) and are associated with a poor outcome. Currently available FLT3 inhibitors have in vitro but limited clinical activity in FLT3-ITD AML. Reports have shown that an arsenic trioxide (ATO)/all-trans-retinoic acid (ATRA) combination improves prognosis in acute promyelocytic leukemia, especially with FLT3-ITD, and ATO or ATRA alone enhances apoptosis in FLT3-ITD AML cells treated with FLT3 inhibitors, providing a rationale to investigate the role of ATO/ATRA in FLT3-ITD AML. Here, we demonstrate that an ATO/ATRA combination selectively exerts synergistic cytotoxicity against FLT3-ITD AML cell lines (MV4;11/MOLM-13). The signaling pathways affected by ATO/ATRA include FLT3/STAT5/MYC, FLT3/STAT5/E2F1, FLT3/ERK/ATF5 and FLT3/AKT/ATF5.ATF5 may function as an oncogene in FLT3-ITD AML. Our findings provide experimental evidence that supports further exploration of ATO/ATRA in FLT3-ITD AML in vivo and warrants a clinical evaluation of regimens comprising an ATO/ATRA combination.
PMID: 28276286 [PubMed - as supplied by publisher]
PMID: 28276286 [PubMed - as supplied by publisher]
関連論文
- ATRA can enhance apoptosis that is induced by Flt3 tyrosine kinase inhibition in Flt3-ITD positive cells.
- Synergistic effect of arsenic trioxide and flt3 inhibition on cells with flt3 internal tandem duplication.
- [Review] [Arsenic trioxide in combination with all-trans retinoic acid for acute promyelocytic leukemia: a systematic review and meta-analysis].
- All-trans retinoic acid synergizes with FLT3 inhibition to eliminate FLT3/ITD+ leukemia stem cells in vitro and in vivo.
- PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukemia treated with ATRA and ATO or ATRA and chemotherapy.