Synergistic Effect of Combination of Flumatinib with Chidamide in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.
10.19746/j.cnki.issn.1009-2137.2025.04.004
- Author:
Chen-Yan YANG
1
;
Chan YANG
1
;
Zheng GE
1
Author Information
1. Department of Hematology, Zhongda Hospital Affiliated to Southeast University, Institute of Hematology Southeast University, Nanjing 210009, Jiangsu Province, China.
- Publication Type:Journal Article
- Keywords:
histone deacetylase inhibitor;
chidamide;
flumatinib;
Philadelphia chromosome-positive acute lymphoblastic leukemia
- MeSH:
Humans;
Aminopyridines/pharmacology*;
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy*;
Apoptosis/drug effects*;
Benzamides/pharmacology*;
Cell Proliferation/drug effects*;
Philadelphia Chromosome;
Drug Synergism;
Cell Line, Tumor;
Signal Transduction;
Pyridines/pharmacology*;
Phosphatidylinositol 3-Kinases/metabolism*
- 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/G1 phase 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.
