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Melanoma is the most lethal cutaneous malignancy that threatens human lives. Poor sensitivity to chemotherapy drugs and the high rate of resistance are the bottlenecks of melanoma treatment. Thus, new chemotherapy drugs are needed. Drug repurposing is a safe, economical and timesaving way to explore new chemotherapy for diseases. Here, we investigated the possibility of repurposing the antibiotic monensin as an anti-melanoma agent. Using three human melanoma cells and two nomal human cell lines as cell models, we found that monensin is obviously toxic to human melanoma cells while safe to nomal human cells. It effectively inhibited cell proliferation and viability, while promoted apoptosis and differentiation of human melanoma cells  in vitro . By establishment of an animal model of transplanted human melanoma in nude mice, we demonstrated that monensin suppressed the growth of xenografts  in vivo . At the same time, we found that melanogenesis increased and the ability of sphere and cloning forming of melanoma decreased under the treatment of monensin. Further detection about differentiation and pluripotent regulations were executed. Our results suggest that monensin is a potent inhibitor of melanoma, and its anti-tumor mechanism may be through promoting the final differentiation of melanoma stem cells and inhibiting their stemness maintenance.

Monensin may inhibit melanoma by regulating the selection between differentiation and stemness of melanoma stem cells