Cell Death Induction by MO2455, a Novel Potential Anti-Cancer Agent in Monocytic and T-Cell Leukemia Cells

Despite advances in targeted therapies, treatment resistance and disease recurrence remain major obstacles in leukemia management. Structural modification of clinically successful kinase inhibitors represents a promising approach for discovering novel anti-leukemic agents with improved biological activities. In the present study, we investigated the anti-leukemic activity and mechanism of action of MO2455, a newly synthesized imatinib-derived compound, in monocytic leukemia U937, THP-1, and T-cell leukemia CCRF-CEM cells. MO2455 showed substantial cytotoxic activity against all three cell lines, with IC₅₀ values of 0.83 μM, 0.43 μM, and 0.57 μM in U937, THP-1, and CCRF-CEM cells, respectively. Treatment with MO2455 induced early mitochondrial membrane depolarization, internucleosomal DNA laddering, a significant accumulation of sub-G1 population and increased Annexin V positivity, suggesting typical apoptosis without cell cycle arrest in U937 cells. MO2455 induced γ-H2AX induction and upregulated the pro-apoptotic NOXA and BBC3 genes. THP-1 and CCRF-CEM cells displayed distinct large DNA fragmentation with smearing. In PBMCs from two healthy donors, IC₅₀ values were 0.99 and 0.60 μM, respectively, although the cells remained morphologically healthy without obvious extensive cell death. Overall, MO2455 exhibits substantial anti-leukemic activity and induces cell death through apoptosis and other mechanisms, supporting further investigation as an anti-leukemic agent.