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A drug screening assay on cancer cells chronically adapted to acidosis

BACKGROUND: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen su...

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Autores principales: Pellegrini, Paola, Serviss, Jason T., Lundbäck, Thomas, Bancaro, Nicolo, Mazurkiewicz, Magdalena, Kolosenko, Iryna, Yu, Di, Haraldsson, Martin, D’Arcy, Padraig, Linder, Stig, De Milito, Angelo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156858/
https://www.ncbi.nlm.nih.gov/pubmed/30263014
http://dx.doi.org/10.1186/s12935-018-0645-5
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author Pellegrini, Paola
Serviss, Jason T.
Lundbäck, Thomas
Bancaro, Nicolo
Mazurkiewicz, Magdalena
Kolosenko, Iryna
Yu, Di
Haraldsson, Martin
D’Arcy, Padraig
Linder, Stig
De Milito, Angelo
author_facet Pellegrini, Paola
Serviss, Jason T.
Lundbäck, Thomas
Bancaro, Nicolo
Mazurkiewicz, Magdalena
Kolosenko, Iryna
Yu, Di
Haraldsson, Martin
D’Arcy, Padraig
Linder, Stig
De Milito, Angelo
author_sort Pellegrini, Paola
collection PubMed
description BACKGROUND: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. METHODS: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. RESULTS: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. CONCLUSIONS: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-018-0645-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-61568582018-09-27 A drug screening assay on cancer cells chronically adapted to acidosis Pellegrini, Paola Serviss, Jason T. Lundbäck, Thomas Bancaro, Nicolo Mazurkiewicz, Magdalena Kolosenko, Iryna Yu, Di Haraldsson, Martin D’Arcy, Padraig Linder, Stig De Milito, Angelo Cancer Cell Int Primary Research BACKGROUND: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. METHODS: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. RESULTS: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. CONCLUSIONS: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12935-018-0645-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-09-25 /pmc/articles/PMC6156858/ /pubmed/30263014 http://dx.doi.org/10.1186/s12935-018-0645-5 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Primary Research
Pellegrini, Paola
Serviss, Jason T.
Lundbäck, Thomas
Bancaro, Nicolo
Mazurkiewicz, Magdalena
Kolosenko, Iryna
Yu, Di
Haraldsson, Martin
D’Arcy, Padraig
Linder, Stig
De Milito, Angelo
A drug screening assay on cancer cells chronically adapted to acidosis
title A drug screening assay on cancer cells chronically adapted to acidosis
title_full A drug screening assay on cancer cells chronically adapted to acidosis
title_fullStr A drug screening assay on cancer cells chronically adapted to acidosis
title_full_unstemmed A drug screening assay on cancer cells chronically adapted to acidosis
title_short A drug screening assay on cancer cells chronically adapted to acidosis
title_sort drug screening assay on cancer cells chronically adapted to acidosis
topic Primary Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156858/
https://www.ncbi.nlm.nih.gov/pubmed/30263014
http://dx.doi.org/10.1186/s12935-018-0645-5
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