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Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway

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 clin...

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Autores principales: Farhan, Mohd, Silva, Marta, Xingan, Xing, Zhou, Zhiwei, Zheng, Wenhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684509/
https://www.ncbi.nlm.nih.gov/pubmed/34931134
http://dx.doi.org/10.1155/2021/9911537
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author Farhan, Mohd
Silva, Marta
Xingan, Xing
Zhou, Zhiwei
Zheng, Wenhua
author_facet Farhan, Mohd
Silva, Marta
Xingan, Xing
Zhou, Zhiwei
Zheng, Wenhua
author_sort Farhan, Mohd
collection PubMed
description 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.
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spelling pubmed-86845092021-12-19 Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway Farhan, Mohd Silva, Marta Xingan, Xing Zhou, Zhiwei Zheng, Wenhua Oxid Med Cell Longev Research Article 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. Hindawi 2021-12-11 /pmc/articles/PMC8684509/ /pubmed/34931134 http://dx.doi.org/10.1155/2021/9911537 Text en Copyright © 2021 Mohd Farhan et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Farhan, Mohd
Silva, Marta
Xingan, Xing
Zhou, Zhiwei
Zheng, Wenhua
Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway
title Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway
title_full Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway
title_fullStr Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway
title_full_unstemmed Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway
title_short Artemisinin Inhibits the Migration and Invasion in Uveal Melanoma via Inhibition of the PI3K/AKT/mTOR Signaling Pathway
title_sort artemisinin inhibits the migration and invasion in uveal melanoma via inhibition of the pi3k/akt/mtor signaling pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8684509/
https://www.ncbi.nlm.nih.gov/pubmed/34931134
http://dx.doi.org/10.1155/2021/9911537
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