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Huidan Zhang,* Dongju Han,* Tongtong Lv, Kehang Liu, Yunqing Yang, Xixi Xu, Yuqing ChenDepartment of Biochemistry, Life Sciences College, Nanjing Normal University, Nanjing, People’s Republic of China*These authors contributed equally to this workPurpose: There is an urgent need for the development of novel, effective, and less toxic drugs to treat leukemia. Antimicrobial peptides (AMPs) have received much more attention as alternative chemotherapeutic agents. This study aimed to examined the cytotoxicity of a novel AMP myristoly-CM4 against chronic myeloid leukemia cells (K562/MDR) and acute lymphocytic leukemia cells (Jurkat), and further investigated its selectivity to clarify the cytotoxic mechanism.Materials and methods: In this study, the cytotoxicity and selectivity of myristoly-CM4 against K562/MDR and Jurkat cells were assessed in vitro, and the anticancer mechanism responsible for its cytotoxicity and selectivity was further investigated.Results: Myristoly-CM4 was cytotoxic to these leukemia cell lines (IC50 2–4 μM) and was less cytotoxic to normal cells (HEK-293, L02 cells, peripheral blood mononuclear cells, and erythrocytes). Myristoyl-CM4 had stronger affinity to K562/MDR and Jurkat cells than to normal cells, while the contents of phosphatidylserine and sialic acids on the cell surfaces of K562/MDR and Jurkat cells were significantly higher than that of HEK293 cells. The myristoyl group effectively mediated the internalization of myristoyl-CM4 to leukemia cells. After internalization, myristoyl-CM4 could target mitochondria and affected mitochondrial function, including disruption of Δψm, increasing the accumulation of ROS, increasing the Bax/Bcl-2 ratio, activating caspase 9 and 3, and PARP to induce mitochondria-dependent apoptosis in both K562/MDR and Jurkat cells. Myristoyl-CM4 also induced K562/MDR cell necrosis by directive membrane disruption, and significantly decreased the level of P-glycoprotein in K562/MDR cells.Conclusion: These results suggested that myristoyl-CM4 showed selective cytotoxicity to leukemia K562/MDR and Jurkat cells by apoptosis and/or necrosis pathway. Myristoyl-CM4, thus, appears to be a promising candidate for leukemia treatment, including multidrug-resistant leukemia.Keywords: leukemia, multi-drug resistance, necrosis, apoptosis, myristoyl-CM4, selectivity &nbsp