Abstract
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.
Highlights
Melanoma is a highly malignant tumor, with mortality as high as 80% (Cummins et al, 2006)
To test whether monensin can decrease the livability of human melanoma, subconfluent A375, Mel-624 and Mel-888 cells were grown in increasing concentrations of monensin
Crystal violet staining results showed that cell proliferation of A375, Mel-624 and Mel-888 cells was significantly inhibited in the monensin-treated groups compared to the control group, especially in A375 cells (Figs. 1A and 1B)
Summary
Melanoma is a highly malignant tumor, with mortality as high as 80% (Cummins et al, 2006). Melanoma is not sensitive to radiotherapy, and the treatment is mainly dependent on chemotherapy. The front-line clinical anticancer agents used for melanoma are mainly in five categories, including alkylating agents, anti-CTLA4 monoclonal antibodies, BRAFV600E inhibitors, CKIT inhibitors and PD-1 inhibitors. Representative drugs include Dacarbazine, Ipilimumab, Vemurafenib, Imatinib and Nivolumab. The natural resistance rate of melanoma in order is 87.5%, 88%, 70% (white) ∼85% (yellow), 98.8% (white) ∼89.2% (yellow), and 74% (Guo et al, 2012; Wu et al, 2014). There is an urgent need to develop effective new drugs. An invention of a new drug usually faces a long research period, large risk of fail and biosafty problems
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