Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

Abstract Paragangliomas (PGLs) are infiltrating autonomic nervous system tumors that cause important morbidity. At present, surgery is the only effective therapeutic option for this rare tumor. Thus, new agents for PGL treatment should be identified. Using unique PGL cell models established in our l...

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Autores principales:	Rosalba Florio, Laura De Lellis, Serena Veschi, Fabio Verginelli, Viviana di Giacomo, Marialucia Gallorini, Silvia Perconti, Mario Sanna, Renato Mariani-Costantini, Angelica Natale, Arduino Arduini, Rosa Amoroso, Amelia Cataldi, Alessandro Cama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Metformin Dichloroacetate (DCA) Paragangliomas (PGL) Unique Cell Model Clonogenic Activity Medicine R Science Q
Acceso en línea:	https://doaj.org/article/153a8c3484424e5094b16382d6f65342
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spelling	oai:doaj.org-article:153a8c3484424e5094b16382d6f653422021-12-02T15:08:52ZEffects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells10.1038/s41598-018-31797-52045-2322https://doaj.org/article/153a8c3484424e5094b16382d6f653422018-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-31797-5https://doaj.org/toc/2045-2322Abstract Paragangliomas (PGLs) are infiltrating autonomic nervous system tumors that cause important morbidity. At present, surgery is the only effective therapeutic option for this rare tumor. Thus, new agents for PGL treatment should be identified. Using unique PGL cell models established in our laboratory, we evaluated the effect of dichloroacetate (DCA) as single agent or in a novel combination with other metabolic drugs, including GW6471 and metformin. DCA and metformin had not been tested before in PGL. DCA reduced PGL cell viability and growth through mechanisms involving reactivation of PDH complex leading to promotion of oxidative metabolism, with lowering of lactate and enhanced ROS production. This resulted in cell cycle inhibition and induction of apoptosis in PGL cells, as shown by flow cytometry and immunoblot analyses. Moreover, DCA drastically impaired clonogenic activity and migration of PGL cells. Also metformin reduced PGL cell viability as single agent and the combinations of DCA, GW6471 and metformin had strong effects on cell viability. Furthermore, combined treatments had drastic and synergistic effects on clonogenic ability. In conclusion, DCA, GW6471 and metformin as single agents and in combination appear to have promising antitumor effects in unique cell models of PGL.Rosalba FlorioLaura De LellisSerena VeschiFabio VerginelliViviana di GiacomoMarialucia GalloriniSilvia PercontiMario SannaRenato Mariani-CostantiniAngelica NataleArduino ArduiniRosa AmorosoAmelia CataldiAlessandro CamaNature PortfolioarticleMetforminDichloroacetate (DCA)Paragangliomas (PGL)Unique Cell ModelClonogenic ActivityMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Metformin Dichloroacetate (DCA) Paragangliomas (PGL) Unique Cell Model Clonogenic Activity Medicine R Science Q
spellingShingle	Metformin Dichloroacetate (DCA) Paragangliomas (PGL) Unique Cell Model Clonogenic Activity Medicine R Science Q Rosalba Florio Laura De Lellis Serena Veschi Fabio Verginelli Viviana di Giacomo Marialucia Gallorini Silvia Perconti Mario Sanna Renato Mariani-Costantini Angelica Natale Arduino Arduini Rosa Amoroso Amelia Cataldi Alessandro Cama Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
description	Abstract Paragangliomas (PGLs) are infiltrating autonomic nervous system tumors that cause important morbidity. At present, surgery is the only effective therapeutic option for this rare tumor. Thus, new agents for PGL treatment should be identified. Using unique PGL cell models established in our laboratory, we evaluated the effect of dichloroacetate (DCA) as single agent or in a novel combination with other metabolic drugs, including GW6471 and metformin. DCA and metformin had not been tested before in PGL. DCA reduced PGL cell viability and growth through mechanisms involving reactivation of PDH complex leading to promotion of oxidative metabolism, with lowering of lactate and enhanced ROS production. This resulted in cell cycle inhibition and induction of apoptosis in PGL cells, as shown by flow cytometry and immunoblot analyses. Moreover, DCA drastically impaired clonogenic activity and migration of PGL cells. Also metformin reduced PGL cell viability as single agent and the combinations of DCA, GW6471 and metformin had strong effects on cell viability. Furthermore, combined treatments had drastic and synergistic effects on clonogenic ability. In conclusion, DCA, GW6471 and metformin as single agents and in combination appear to have promising antitumor effects in unique cell models of PGL.
format	article
author	Rosalba Florio Laura De Lellis Serena Veschi Fabio Verginelli Viviana di Giacomo Marialucia Gallorini Silvia Perconti Mario Sanna Renato Mariani-Costantini Angelica Natale Arduino Arduini Rosa Amoroso Amelia Cataldi Alessandro Cama
author_facet	Rosalba Florio Laura De Lellis Serena Veschi Fabio Verginelli Viviana di Giacomo Marialucia Gallorini Silvia Perconti Mario Sanna Renato Mariani-Costantini Angelica Natale Arduino Arduini Rosa Amoroso Amelia Cataldi Alessandro Cama
author_sort	Rosalba Florio
title	Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
title_short	Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
title_full	Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
title_fullStr	Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
title_full_unstemmed	Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells
title_sort	effects of dichloroacetate as single agent or in combination with gw6471 and metformin in paraganglioma cells
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/153a8c3484424e5094b16382d6f65342
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Effects of dichloroacetate as single agent or in combination with GW6471 and metformin in paraganglioma cells

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