Icaritin enhances the anti-leukemic activity of imatinib in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia cells: functional involvement of PI3K/AKT signaling

Objectives To determine whether icaritin (ICA) enhances imatinib (IM) activity in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL) cells and the role of PI3K/AKT signaling in this process.Methods SUP-B15 and TOM-1 cells underwent 48-hour single-agent concentration-response testing and complete 7 × 7 ICA × IM matrix analysis using the zero interaction potency (ZIP) model. Apoptosis, mitochondrial membrane potential andPI3K/AKT/FOXO1 signaling were assessed. SUP-B15 rescue experiments included the PI3K-activating peptide 740Y-P alone and with ICA + IM.Results In SUP-B15 cells, the fitted IM and ICA IC50 values were 8.707 μM and 36.70 μM , respectively. ZIP scores indicated a reproducible but borderline/modest positive interaction. In TOM-1 cells, the fitted IM and ICA IC50 values were 13.32 μM and 44.31 μM , with ZIP scores consistently within the additive range. ICA + IM produced the highest mean apoptotic fraction in both models. In SUP-B15 cells, combined treatment was associated with mitochondrial depolarization, reduced PI3K/AKT/FOXO1 phosphorylation, and increased nuclear FOXO1, BIM, and p27. 740Y-P partially reversed these effects. TOM-1 reproduced several responses, although P-AKT/AKT was not further reduced relative to either monotherapy.Discussion ICA enhanced IM activity in both Ph+ B-ALL cell models, but the interaction classification was model-dependent. Partial pharmacological rescue supports PI3K/AKT involvement without establishing pathway exclusivity, a direct ICA target, or reversal of established IM resistance.Conclusion ICA enhances IM activity in the two Ph+ B-ALL cell models examined. Replicate-level ZIP analysis supports a borderline/modest positive interaction in SUP-B15 and an additive interaction in TOM-1. Further validation in resistant models, primary cells, normal hematopoietic cells, and in vivo systems is required before translational inference.