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Archive > Volume 33 Issue 8 > 2026,33(8):848-856. DOI:10.3872/j.issn.1007-385X.2026.08.005 Prev Next
Basic Research
Inhibitory effects and underlying mechanisms of imatinib combined with PRI-724 on BCR-ABL1-positive chronic myeloid leukemia cells and xenograft models
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Abstract:
Objective: To investigate the antitumor effects and potential mechanisms of the β-catenin/CREB-binding protein (CBP) pathway inhibitor PRI-724 combined with imatinib in BCR-ABL1-positive chronic myeloid leukemia (CML) cells and xenograft models. Methods: Human K562 cells and murine 32D myeloid cells stably expressing wild-type BCR-ABL1 (32D-WT) or T315I-mutant BCR-ABL1 (32D-T315I) were used for in vitro experiments. The effects of imatinib, PRI-724, and their combination on cell viability were detected using the CCK-8 assay, and the half-maximal inhibitory concentration (IC50) and combination index (CI) were calculated. Senescence-associated phenotypes were examined by SA-β-gal staining. Co-immunoprecipitation (Co-IP) was used to detect the effect of PRI-724 on the interaction between β-catenin and CBP/p300. For in vivo experiments, subcutaneous xenograft models were established in nude mice using K562, 32D-WT, and 32D-T315I cells. Untreated, imatinib, PRI?724, and imatinib + PRI?724 groups were established, and each group received the corresponding treatment, and tumor growth was monitored. The in vivo CI was calculated based on tumor growth inhibition (TGI). WB was used to detect the expression of PI3K/AKT signaling pathway-related proteins, nuclear β-catenin/CBP, and downstream effectors c-Myc and Cyclin D1 in tumor tissues. Results: Imatinib and PRI-724 inhibited K562, 32D-WT, and 32D-T315I cells in a concentration-dependent manner. The IC50 values of imatinib in K562, 32D-WT, and 32D- T315I cells were 0.860, 0.594, and 1.646 μmol/L, respectively; the IC50 values of PRI-724 in the above three cell types were 1.120, 0.761, and 0.756 μmol/L, respectively. Compared with 32D-WT cells, 32D-T315I cells showed reduced sensitivity to imatinib, whereas no obvious decrease in sensitivity to PRI-724 was observed. The CI values of imatinib + PRI-724 in K562, 32D-WT, and 32D-T315I cells were 0.635, 0.780, and 0.689, respectively, suggesting a synergistic inhibitory effect in vitro. SA- β-gal staining showed that, compared with imatinib monotherapy, PRI-724 monotherapy increased the proportion of SA- β-gal-positive cells in all three cell models, and the combination further increased this proportion. Co-IP results showed that, after PRI-724 treatment, the level of CBP co-precipitated with β-catenin was decreased, whereas the level of p300 co-precipitated with β-catenin was increased. In vivo experiments showed that, compared with the imatinib monotherapy group, the imatinib + PRI-724 combination group showed further reductions in tumor volume and tumor weight. However, the in vivo CI values calculated using the TGI-based response-additivity approach in the K562, 32D-WT, and 32D-T315I xenograft models were all > 1, suggesting that, under the current dose and administration regimen, the in vivo combination effect of the two drugs did not reach the expected additive effect and may have shown an antagonistic trend. WB showed that, compared with the imatinib monotherapy group, the combination treatment group had lower p-PI3K/PI3K and p-AKT/ AKT ratios and lower expression levels of nuclear β-catenin, CBP, c-Myc, and Cyclin D1 in tumor tissues. Conclusion: PRI-724 combined with imatinib exhibits a synergistic inhibitory effect in vitro and further suppresses tumor growth in vivo compared with imatinib monotherapy. The underlying mechanism may be related to modulation of the β-catenin/CBP/p300 complex, inhibition of the PI3K/AKT signaling pathway, and downregulation of c-Myc and Cyclin D1 expression.
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