Isoimperatorin inhibits cell proliferation and induces apoptosis via regulating PI3K/AKT pathway in acute lymphoblastic leukemia.

[OBJECTIVES] This study aims to explore whether isoimperatorin (ISOIM) regulates the malignant phenotype of T‑cell acute lymphoblastic leukemia (T-ALL) cells through the PI3K/AKT pathway and programmed cell death ligand-1 (PD-L1).

[METHODS] Through in vitro experiments, ISOIM on T-ALL cell proliferation and apoptosis was evaluated using the cell counting kit-8 and EdU assays, flow cytometry, and TUNEL staining. Network pharmacology, molecular docking, and functional enrichment analyses were conducted to analyze the underlying mechanisms of ISOIM. Changes in apoptosis-related proteins, PD-L1 protein, and PI3K/AKT pathway-related proteins were assessed by western blotting.

[RESULTS] ISOIM inhibited T-ALL cell proliferation, promoted apoptosis, decreased Bcl-2 levels, and increased C-caspase-3 and Bax levels. KEGG and GO enrichment analyses indicated that the overlapping targets between ISOIM and ALL were related to the PD-1 checkpoint and PI3K/AKT pathway. Molecular docking analysis showed good binding between ISOIM and PIK3CA (also known as PI3K). ISOIM reduced PD-L1, p-PI3K, p-AKT, and p-mTOR levels. Moreover, the PI3K/AKT pathway activator 740 Y-P reversed the inhibitory effect of ISOIM on PD-L1 expression and the malignant behavior of T-ALL cells.

[CONCLUSIONS] ISOIM inhibited the malignant behavior of T-ALL cells and reduced PD-L1 levels by suppressing the PI3K/AKT pathway. This study provides a theoretical basis for developing novel treatment strategies for ALL.