Abstract
Uveal melanoma is the most common primary ocular neoplasm in adults, with many patients ending up developing liver metastasis and facing a significant reduction of their life expectancy due to the lack of efficient treatments. Artemisinin is an antimalarial drug that has been widely used in the clinic and whose anticancer properties have also been described. Its reported safety, affordability, and ability to reach the ocular tissues point that it has a potential therapeutic agent against uveal melanoma. In the present study, we found that a subantimalaria dosage of artemisinin significantly attenuated the migration and invasion potential of uveal melanoma cells, in a concentration-dependent manner. Assessment of the mechanisms underlying artemisinin anticancer action revealed that its use dramatically reduced the phosphorylation of PI3K, AKT, and mTOR in UM cells. Further inhibition of PI3K signaling, using LY294002, or of mTOR, by rapamycin, blocked the migration and invasion of UM cells similarly to artemisinin. In contrast, AKT or mTOR activator (Sc79 and MHY1485, respectively) attenuated the inhibitory effect of artemisinin on the migration and invasion abilities of UM cells, further validating that artemisinin's anticancer effect is likely to be mediated via inhibition of the PI3K/AKT/mTOR pathway. Artemisinin also induced mitochondrial membrane potential loss and apoptosis of UM cells, having no significant toxic effect on normal retinal neuronal cells RGC-5 and epithelial cells D407. These findings and the reported safety of artemisinin's clinical dosage strongly suggest the therapeutic potential of artemisinin in the prevention and treatment of uveal melanomas.