Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma

Abstract The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the di...

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Autores principales:	Cecilie Abildgaard, Salvatore Rizza, Helle Christiansen, Steffen Schmidt, Christina Dahl, Ahmad Abdul-Al, Annette Christensen, Giuseppe Filomeni, Per Guldberg
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1b24ea4a0dc64c8fbd2d5e8ec70458cd
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spelling	oai:doaj.org-article:1b24ea4a0dc64c8fbd2d5e8ec70458cd2021-12-02T14:28:19ZScreening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma10.1038/s41598-021-83796-82045-2322https://doaj.org/article/1b24ea4a0dc64c8fbd2d5e8ec70458cd2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-83796-8https://doaj.org/toc/2045-2322Abstract The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.Cecilie AbildgaardSalvatore RizzaHelle ChristiansenSteffen SchmidtChristina DahlAhmad Abdul-AlAnnette ChristensenGiuseppe FilomeniPer GuldbergNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cecilie Abildgaard Salvatore Rizza Helle Christiansen Steffen Schmidt Christina Dahl Ahmad Abdul-Al Annette Christensen Giuseppe Filomeni Per Guldberg Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
description	Abstract The prognosis of metastatic melanoma remains poor due to de novo or acquired resistance to immune and targeted therapies. Previous studies have shown that melanoma cells have perturbed metabolism and that cellular metabolic pathways represent potential therapeutic targets. To support the discovery of new drug candidates for melanoma, we examined 180 metabolic modulators, including phytochemicals and anti-diabetic compounds, for their growth-inhibitory activities against melanoma cells, alone and in combination with the BRAF inhibitor vemurafenib. Two positive hits from this screen, 4-methylumbelliferone (4-MU) and ursolic acid (UA), were subjected to validation and further characterization. Metabolic analysis showed that 4-MU affected cellular metabolism through inhibition of glycolysis and enhanced the effect of vemurafenib to reduce the growth of melanoma cells. In contrast, UA reduced mitochondrial respiration, accompanied by an increase in the glycolytic rate. This metabolic switch potentiated the growth-inhibitory effect of the pyruvate dehydrogenase kinase inhibitor dichloroacetate. Both drug combinations led to increased production of reactive oxygen species, suggesting the involvement of oxidative stress in the cellular response. These results support the potential use of metabolic modulators for combination therapies in cancer and may encourage preclinical validation and clinical testing of such treatment strategies in patients with metastatic melanoma.
format	article
author	Cecilie Abildgaard Salvatore Rizza Helle Christiansen Steffen Schmidt Christina Dahl Ahmad Abdul-Al Annette Christensen Giuseppe Filomeni Per Guldberg
author_facet	Cecilie Abildgaard Salvatore Rizza Helle Christiansen Steffen Schmidt Christina Dahl Ahmad Abdul-Al Annette Christensen Giuseppe Filomeni Per Guldberg
author_sort	Cecilie Abildgaard
title	Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
title_short	Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
title_full	Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
title_fullStr	Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
title_full_unstemmed	Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
title_sort	screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1b24ea4a0dc64c8fbd2d5e8ec70458cd
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Screening of metabolic modulators identifies new strategies to target metabolic reprogramming in melanoma

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