Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M

Aragó, Marc; Moreno Felici, Juan; Abás Prades, Sònia; Rodríguez Arévalo, Sergio; Hyrossová, Petra; Figueras i Amat, Agnès; Viñals Canals, Francesc; Pérez, Belén; Loza, María Isabel; Brea, José; Latorre, Pedro; Carrodeguas, Jose A.; García-Roves, Pablo M. (Pablo Miguel); Galdeano Cantador, Carlos; Ginex, Tiziana; Luque Garriga, F. Xavier; Escolano Mirón, Carmen; Perales Losa, Carlos

Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M

Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pa...

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Autores:	Aragó, Marc, Moreno Felici, Juan, Abás Prades, Sònia, Rodríguez Arévalo, Sergio, Hyrossová, Petra, Figueras i Amat, Agnès, Viñals Canals, Francesc, Pérez, Belén, Loza, María Isabel, Brea, José, Latorre, Pedro, Carrodeguas, Jose A., García-Roves, Pablo M. (Pablo Miguel), Galdeano Cantador, Carlos, Ginex, Tiziana, Luque Garriga, F. Xavier, Escolano Mirón, Carmen, Perales Losa, Carlos
Tipo de recurso:	artículo
Estado:	Versión publicada
Fecha de publicación:	2020
País:	España
Institución:	Universidad de Barcelona
Repositorio:	Dipòsit Digital de la UB
OAI Identifier:	oai:diposit.ub.edu:2445/174403
Acceso en línea:	https://hdl.handle.net/2445/174403
Access Level:	acceso abierto
Palabra clave:	Tractament adjuvant del càncer Farmacologia Càncer de mama Càncer colorectal Adjuvant treatment of cancer Pharmacology Breast cancer Colorectal cancer

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spelling	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-MAragó, MarcMoreno Felici, JuanAbás Prades, SòniaRodríguez Arévalo, SergioHyrossová, PetraFigueras i Amat, AgnèsViñals Canals, FrancescPérez, BelénLoza, María IsabelBrea, JoséLatorre, PedroCarrodeguas, Jose A.García-Roves, Pablo M. (Pablo Miguel)Galdeano Cantador, CarlosGinex, TizianaLuque Garriga, F. XavierEscolano Mirón, CarmenPerales Losa, CarlosTractament adjuvant del càncerFarmacologiaCàncer de mamaCàncer colorectalAdjuvant treatment of cancerPharmacologyBreast cancerColorectal cancerBackground: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor.Elsevier Masson SAS2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/174403Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.biopha.2019.109601Biomedicine & Pharmacotherapy, 2020, vol. 121, num. 109601https://doi.org/10.1016/j.biopha.2019.109601cc by nc-nd (c) Aragó, Marc et al., 2020http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1744032026-05-27T06:46:51Z
dc.title.none.fl_str_mv	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
title	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
spellingShingle	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M Aragó, Marc Tractament adjuvant del càncer Farmacologia Càncer de mama Càncer colorectal Adjuvant treatment of cancer Pharmacology Breast cancer Colorectal cancer
title_short	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
title_full	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
title_fullStr	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
title_full_unstemmed	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
title_sort	Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M
dc.creator.none.fl_str_mv	Aragó, Marc Moreno Felici, Juan Abás Prades, Sònia Rodríguez Arévalo, Sergio Hyrossová, Petra Figueras i Amat, Agnès Viñals Canals, Francesc Pérez, Belén Loza, María Isabel Brea, José Latorre, Pedro Carrodeguas, Jose A. García-Roves, Pablo M. (Pablo Miguel) Galdeano Cantador, Carlos Ginex, Tiziana Luque Garriga, F. Xavier Escolano Mirón, Carmen Perales Losa, Carlos
author	Aragó, Marc
author_facet	Aragó, Marc Moreno Felici, Juan Abás Prades, Sònia Rodríguez Arévalo, Sergio Hyrossová, Petra Figueras i Amat, Agnès Viñals Canals, Francesc Pérez, Belén Loza, María Isabel Brea, José Latorre, Pedro Carrodeguas, Jose A. García-Roves, Pablo M. (Pablo Miguel) Galdeano Cantador, Carlos Ginex, Tiziana Luque Garriga, F. Xavier Escolano Mirón, Carmen Perales Losa, Carlos
author_role	author
author2	Moreno Felici, Juan Abás Prades, Sònia Rodríguez Arévalo, Sergio Hyrossová, Petra Figueras i Amat, Agnès Viñals Canals, Francesc Pérez, Belén Loza, María Isabel Brea, José Latorre, Pedro Carrodeguas, Jose A. García-Roves, Pablo M. (Pablo Miguel) Galdeano Cantador, Carlos Ginex, Tiziana Luque Garriga, F. Xavier Escolano Mirón, Carmen Perales Losa, Carlos
author2_role	author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	Tractament adjuvant del càncer Farmacologia Càncer de mama Càncer colorectal Adjuvant treatment of cancer Pharmacology Breast cancer Colorectal cancer
topic	Tractament adjuvant del càncer Farmacologia Càncer de mama Càncer colorectal Adjuvant treatment of cancer Pharmacology Breast cancer Colorectal cancer
description	Background: Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate. The mitochondrial isozyme, PEPCK-M is highly expressed in cancer cells, where it plays a role in nutrient stress response. To date, pharmacological strategies to target this pathway have not been pursued. Methods: A compound embodying a 3-alkyl-1,8-dibenzylxanthine nucleus (iPEPCK-2), was synthesized and successfully probed in silico on a PEPCK-M structural model. Potency and target engagement in vitro and in vivo were evaluated by kinetic and cellular thermal shift assays (CETSA). The compound and its target were validated in tumor growth models in vitro and in murine xenografts. Results: Cross-inhibitory capacity and increased potency as compared to 3-MPA were confirmed in vitro and in vivo. Treatment with iPEPCK-2 inhibited cell growth and survival, especially in poor-nutrient environment, consistent with an impact on colony formation in soft agar. Finally, daily administration of the PEPCK-M inhibitor successfully inhibited tumor growth in two murine xenograft models as compared to vehicle, without weight loss, or any sign of apparent toxicity. Conclusion: We conclude that iPEPCK-2 is a compelling anticancer drug targeting PEPCK-M, a hallmark gene product involved in metabolic adaptations of the tumor.
publishDate	2020
dc.date.none.fl_str_mv	2020
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://hdl.handle.net/2445/174403
url	https://hdl.handle.net/2445/174403
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	Reproducció del document publicat a: https://doi.org/10.1016/j.biopha.2019.109601 Biomedicine & Pharmacotherapy, 2020, vol. 121, num. 109601 https://doi.org/10.1016/j.biopha.2019.109601
dc.rights.none.fl_str_mv	cc by nc-nd (c) Aragó, Marc et al., 2020 http://creativecommons.org/licenses/by-nc-nd/3.0/es/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	cc by nc-nd (c) Aragó, Marc et al., 2020 http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv	openAccess
dc.format.none.fl_str_mv	application/pdf
dc.publisher.none.fl_str_mv	Elsevier Masson SAS
publisher.none.fl_str_mv	Elsevier Masson SAS
dc.source.none.fl_str_mv	Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia) reponame:Dipòsit Digital de la UB instname:Universidad de Barcelona
instname_str	Universidad de Barcelona
reponame_str	Dipòsit Digital de la UB
collection	Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Pharmacology and preclinical validation of a novel anticancer compound targeting PEPCK-M

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