ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma

Resistance against anti-cancer therapy is one of the major challenges during treatment of multiple cancers. Gemcitabine is a standard first-line chemotherapeutic drug, yet autophagy is highly activated in the hypoxic microenvironment of solid tumors and enhances the survival of tumor cells against g...

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Autores principales:	Farnaz Sedigheh Takhsha, Christel Vangestel, Muhammet Tanc, Sven De Bruycker, Maya Berg, Isabel Pintelon, Sigrid Stroobants, Guido R. Y. De Meyer, Pieter Van Der Veken, Wim Martinet
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	pancreatic ductal adenocarcinoma autophagy ATG4B UAMC-2526 gemcitabine proliferation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/55fbe685450a4b71836730ffe552e10b
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spelling	oai:doaj.org-article:55fbe685450a4b71836730ffe552e10b2021-11-18T08:56:08ZATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma2234-943X10.3389/fonc.2021.750259https://doaj.org/article/55fbe685450a4b71836730ffe552e10b2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.750259/fullhttps://doaj.org/toc/2234-943XResistance against anti-cancer therapy is one of the major challenges during treatment of multiple cancers. Gemcitabine is a standard first-line chemotherapeutic drug, yet autophagy is highly activated in the hypoxic microenvironment of solid tumors and enhances the survival of tumor cells against gemcitabine chemotherapy. Recently, we showed the add-on effect of autophagy inhibitor UAMC-2526 to prevent HT-29 colorectal tumor growth in CD1-/- Foxn1nu mice treated with oxaliplatin. In this study, we aimed to investigate the potential beneficial effects of UAMC-2526 in a syngeneic Panc02 mouse model of pancreatic ductal adenocarcinoma (PDAC). Our data showed that UAMC-2526 combined with gemcitabine significantly reduced tumor growth as compared to the individual treatments. However, in contrast to in vitro experiments with Panc02 cells in culture, we were unable to detect autophagy inhibition by UAMC-2526 in Panc02 tumor tissue, neither via western blot analysis of autophagy markers LC3 and p62, nor by transmission electron microscopy. In vitro experiments revealed that UAMC-2526 enhances the potential of gemcitabine to inhibit Panc02 cell proliferation without obvious induction of cell death. Altogether, we conclude that although the combination treatment of UAMC-2526 with gemcitabine did not inhibit autophagy in the Panc02 mouse model, it has a beneficial effect on tumor growth inhibition.Farnaz Sedigheh TakhshaChristel VangestelChristel VangestelMuhammet TancMuhammet TancSven De BruyckerSven De BruyckerMaya BergIsabel PintelonSigrid StroobantsSigrid StroobantsGuido R. Y. De MeyerGuido R. Y. De MeyerPieter Van Der VekenPieter Van Der VekenWim MartinetWim MartinetFrontiers Media S.A.articlepancreatic ductal adenocarcinomaautophagyATG4BUAMC-2526gemcitabineproliferationNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	pancreatic ductal adenocarcinoma autophagy ATG4B UAMC-2526 gemcitabine proliferation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	pancreatic ductal adenocarcinoma autophagy ATG4B UAMC-2526 gemcitabine proliferation Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Farnaz Sedigheh Takhsha Christel Vangestel Christel Vangestel Muhammet Tanc Muhammet Tanc Sven De Bruycker Sven De Bruycker Maya Berg Isabel Pintelon Sigrid Stroobants Sigrid Stroobants Guido R. Y. De Meyer Guido R. Y. De Meyer Pieter Van Der Veken Pieter Van Der Veken Wim Martinet Wim Martinet ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma
description	Resistance against anti-cancer therapy is one of the major challenges during treatment of multiple cancers. Gemcitabine is a standard first-line chemotherapeutic drug, yet autophagy is highly activated in the hypoxic microenvironment of solid tumors and enhances the survival of tumor cells against gemcitabine chemotherapy. Recently, we showed the add-on effect of autophagy inhibitor UAMC-2526 to prevent HT-29 colorectal tumor growth in CD1-/- Foxn1nu mice treated with oxaliplatin. In this study, we aimed to investigate the potential beneficial effects of UAMC-2526 in a syngeneic Panc02 mouse model of pancreatic ductal adenocarcinoma (PDAC). Our data showed that UAMC-2526 combined with gemcitabine significantly reduced tumor growth as compared to the individual treatments. However, in contrast to in vitro experiments with Panc02 cells in culture, we were unable to detect autophagy inhibition by UAMC-2526 in Panc02 tumor tissue, neither via western blot analysis of autophagy markers LC3 and p62, nor by transmission electron microscopy. In vitro experiments revealed that UAMC-2526 enhances the potential of gemcitabine to inhibit Panc02 cell proliferation without obvious induction of cell death. Altogether, we conclude that although the combination treatment of UAMC-2526 with gemcitabine did not inhibit autophagy in the Panc02 mouse model, it has a beneficial effect on tumor growth inhibition.
format	article
author	Farnaz Sedigheh Takhsha Christel Vangestel Christel Vangestel Muhammet Tanc Muhammet Tanc Sven De Bruycker Sven De Bruycker Maya Berg Isabel Pintelon Sigrid Stroobants Sigrid Stroobants Guido R. Y. De Meyer Guido R. Y. De Meyer Pieter Van Der Veken Pieter Van Der Veken Wim Martinet Wim Martinet
author_facet	Farnaz Sedigheh Takhsha Christel Vangestel Christel Vangestel Muhammet Tanc Muhammet Tanc Sven De Bruycker Sven De Bruycker Maya Berg Isabel Pintelon Sigrid Stroobants Sigrid Stroobants Guido R. Y. De Meyer Guido R. Y. De Meyer Pieter Van Der Veken Pieter Van Der Veken Wim Martinet Wim Martinet
author_sort	Farnaz Sedigheh Takhsha
title	ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma
title_short	ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma
title_full	ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma
title_fullStr	ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma
title_full_unstemmed	ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma
title_sort	atg4b inhibitor uamc-2526 potentiates the chemotherapeutic effect of gemcitabine in a panc02 mouse model of pancreatic ductal adenocarcinoma
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/55fbe685450a4b71836730ffe552e10b
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ATG4B Inhibitor UAMC-2526 Potentiates the Chemotherapeutic Effect of Gemcitabine in a Panc02 Mouse Model of Pancreatic Ductal Adenocarcinoma

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