The Synergistic Anti-Leukemia Effect of Bcl-2 Inhibitor Combined with HDAC Inhibitor by PI3K/AKT/FoxO1 Axis in T-Cell Acute Lymphoblastic Leukemia
10.19746/j.cnki.issn1009-2137.2025.06.008
- VernacularTitle:Bcl-2抑制剂协同HDAC抑制剂通过PI3K/AKT/FoxO1轴抗急性T淋巴细胞白血病机制研究
- Author:
Dan-Dan SONG
1
;
Si-Yu GU
;
Chun-Hua SONG
;
Zheng GE
Author Information
1. 东南大学附属中大医院血液科,东南大学血液病研究所,江苏南京 210009
- Publication Type:Journal Article
- Keywords:
venetoclax;
chidamide;
T-cell acute lymphoblastic leukemia;
FoxO1
- From:
Journal of Experimental Hematology
2025;33(6):1599-1608
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To investigate the mechanism of the synergistic anti-leukemia effect of the combination of Bcl-2 inhibitor venetoclax(VEN)and histone deacetylase(HDAC)inhibitor chidamide(CDM)in T-cell acute lymphoblastic leukemia(T-ALL).Methods:The effect of VEN combined with CDM on the proliferation of T-ALL CEM and MOLT-4 cell lines was detected by CCK-8 assay.And the effects on the cell cycle and apoptosis were detected by flow cytometry.Cell cycle protein and apoptosis-related protein expression were detected by Western blot.The key pathways of VEN combined with CDM in T-ALL were screened through network pharmacology analysis,and verifying them in T-ALL cell lines,T-ALL patient cells and public databases.Results:VEN combined with CDM displayed a synergistic effect on cell proliferation of CEM and MOLT-4 cells.In cell cycle experiment,VEN combined with CDM induced G0/G1 phase arrest in CEM and MOLT-4 cells.Western blot experiment showed that VEN combined with CDM could significantly downregulate the expression of cyclin E2 and CDK2 and upregulate the expression of p21Waf1/Cip1.In the apoptosis experiment,VEN combined with CDM could significantly induce the apoptosis of CEM and MOLT-4 cells.Western blot experiment demonstrated that VEN combined with CDM promoted endogenous apoptosis by downregulating Mcl-1 and upregulating Bax and cleaved caspase-3 protein levels.Network pharmacology analysis identified 10 hub genes.KEGG enrichment analysis revealed the cell cycle,PI3K-AKT signaling pathway,and its downstream FoxO signaling pathway were significantly enriched.GO enrichment analysis revealed the G1/S transition of mitotic cell cycle,cyclin-dependent protein kinase holoenzyme complex,and kinase activity were significantly enriched.Western blot experiment showed that VEN combined with CDM could significantly downregulate the protein level of PI3K,AKT,and p-AKT,and upregulate FoxO1 in CEM and MOLT-4 cells.In T-ALL patients,FoxO1 showed significantly lower expression compared to the normal donors,and the same result was verified in the GSE13159 and GSE26713 datasets.Conclusion:The combination of VEN and CDM exerts synergistic anti-leukemia effects by inhibiting cellular proliferation,inducing G0/G1,phase arrest and promoting apoptosis through PI3K/AKT/FoxO1 axis in T-ALL.
