Synergistic Effect of Combination of Flumatinib with Chidamide in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
10.19746/j.cnki.issn1009-2137.2025.04.004
- VernacularTitle:氟马替尼联合西达本胺抗Ph阳性急性淋巴细胞白血病协同效应研究
- Author:
Chen-Yan YANG
1
;
Chan YANG
1
;
Zheng GE
1
Author Information
1. 东南大学附属中大医院血液科,东南大学血液病学研究所,江苏南京 210009
- Publication Type:Journal Article
- Keywords:
histone deacetylase inhibitor;
chidamide;
flumatinib;
Philadelphia chromosome-positive acute lymphoblastic leukemia
- From:
Journal of Experimental Hematology
2025;33(4):951-960
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the synergistic effect of flumatinib(FLU)combined with histone deacetylase inhibitor chidamide(CHI)and underlying mechanism on Philadelphia chromosome-positive acute lymphoblastic leukemia(Ph+ALL)SUP-B15 cells.Methods:CCK-8 method was used to examine the effects of FLU,CHI alone and combination therapy on the proliferation of SUP-B15 cells.Flow cytometry was utilized to analyze the cell cycle and apoptosis.RT-qPCR and Western blot methods were performed to detect target gene expression.Results:FLU combined with CHI significantly inhibited the proliferation,induced G0/G1phase arrest,and increased the apoptosis rate in SUP-B15 cells compared with FLU and CHI alone.The 50 genes were identified by overlapping the two drugs'targets of action with Ph+ALL oncogenic genes in the public databases,and p53 and c-Myc transcription factors and PI3K/AKT signaling pathways were enriched in the overlapped genes.The combination of FLU and CHI significantly reduced the mRNA level of BCR::ABL fusion gene,up-regulated the protein and mRNA levels of p53,BAX,and Caspase-3,and down-regulated the protein and mRNA levels of c-Myc,PIK3CA,PIK3CB,and AKT2 compared with single-drug therapy.The analysis of GEO database and our center cohort showed that c-Myc,PIK3CA,PIK3CB,and AKT2 were significantly up-regulated while p53 was down-regulated in Ph+ALL patients compared to healthy controls.Conclusion:FLU combined with CHI synergistically inhibits cell proliferation,promotes apoptosis,and induces cycle arrest by targeting the PI3K/AKT signaling pathway through the p53/c-Myc axis in Ph+ALL.
