Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth

Abstract We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activit...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Audrey Hébert, Maxime Parisotto, Marie-Camille Rowell, Alexandra Doré, Ana Fernandez Ruiz, Guillaume Lefrançois, Paloma Kalegari, Gerardo Ferbeyre, Andreea R. Schmitzer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6a200413183b471cb0be937679e2ef46
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:6a200413183b471cb0be937679e2ef46
record_format	dspace
spelling	oai:doaj.org-article:6a200413183b471cb0be937679e2ef462021-12-02T17:02:13ZPhenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth10.1038/s41598-021-87993-32045-2322https://doaj.org/article/6a200413183b471cb0be937679e2ef462021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87993-3https://doaj.org/toc/2045-2322Abstract We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD+/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.Audrey HébertMaxime ParisottoMarie-Camille RowellAlexandra DoréAna Fernandez RuizGuillaume LefrançoisPaloma KalegariGerardo FerbeyreAndreea R. SchmitzerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Audrey Hébert Maxime Parisotto Marie-Camille Rowell Alexandra Doré Ana Fernandez Ruiz Guillaume Lefrançois Paloma Kalegari Gerardo Ferbeyre Andreea R. Schmitzer Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
description	Abstract We present the design and synthesis of a small library of substituted biguanidium salts and their capacity to inhibit the growth of pancreatic cancer cells. We first present their in vitro and membrane activity, before we address their mechanism of action in living cells and in vivo activity. We show that phenylethynyl biguanidium salts possess higher ability to cross hydrophobic barriers, improve mitochondrial accumulation and anticancer activity. Mechanistically, the most active compound, 1b, like metformin, activated AMPK, decreased the NAD+/NADH ratio and mitochondrial respiration, but at 800-fold lower concentration. In vivo studies show that compound 1b significantly inhibits the growth of pancreatic cancer xenografts in mice, while biguanides currently in clinical trials had little activity.
format	article
author	Audrey Hébert Maxime Parisotto Marie-Camille Rowell Alexandra Doré Ana Fernandez Ruiz Guillaume Lefrançois Paloma Kalegari Gerardo Ferbeyre Andreea R. Schmitzer
author_facet	Audrey Hébert Maxime Parisotto Marie-Camille Rowell Alexandra Doré Ana Fernandez Ruiz Guillaume Lefrançois Paloma Kalegari Gerardo Ferbeyre Andreea R. Schmitzer
author_sort	Audrey Hébert
title	Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
title_short	Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
title_full	Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
title_fullStr	Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
title_full_unstemmed	Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
title_sort	phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6a200413183b471cb0be937679e2ef46
work_keys_str_mv	AT audreyhebert phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT maximeparisotto phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT mariecamillerowell phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT alexandradore phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT anafernandezruiz phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT guillaumelefrancois phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT palomakalegari phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT gerardoferbeyre phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth AT andreearschmitzer phenylethynylbenzylmodifiedbiguanidesinhibitpancreaticcancertumorgrowth
_version_	1718381910357442560

Phenylethynylbenzyl-modified biguanides inhibit pancreatic cancer tumor growth

Ejemplares similares