Repositioning miconazole: a novel drug for inducing cell death and differentiation in myeloid leukemia

Myeloid leukemia is a common form of blood cancer worldwide. Myeloid cell leukemia-1 (MCL-1), an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family, is frequently overexpressed in various solid tumors and hematological cancers. Miconazole, a broad-spectrum anti-fungal agent, has exhibited anti-tumor properties against multiple cancer types, but its specific effects on leukemia remain unknown. The purpose of our research is to investigate whether miconazole targets MCL-1 to exert an anti-leukemic effect. Our research has demonstrated that miconazole directly binds to MCL-1 in HL60 and K562 cells, significantly inhibiting cell growth and decreasing MCL-1 protein levels, presumably by promoting MCL-1 degradation. Miconazole induces apoptosis, autophagy, and the production of reactive oxygen species (ROS). However, these effects can be attenuated by Z-VAD-FMK, 3-methyladenine (3-MA), and N-acetyl-L-cysteine (NAC). Meanwhile, miconazole-induced reduction of MCL-1 protein is reversed. Animal studies confirm the anti-myelocytic leukemia efficacy of miconazole in vivo. Unexpectedly, at low concentrations and with prolonged exposure, miconazole also promotes cell differentiation. This differentiation effect is positively associated with autophagy and ROS accumulation induced by miconazole, without altering MCL-1 expression. In conclusion, miconazole, identified through a drug repositioning (DR) approach, might be a potential therapeutic candidate for myeloid leukemia by either facilitating cell death or promoting cell differentiation.