[Synergistic Effect of Combination of Flumatinib with Chidamide in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia].

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 G/G 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 and 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 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 , and were significantly up-regulated while 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 axis in Ph ALL.