Cargando…

Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma

BACKGROUND: Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. METHODS: We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Opti...

Descripción completa

Detalles Bibliográficos
Autores principales: Rausch, Magdalena, Weiss, Andrea, Achkhanian, Joanna, Rotari, Andrei, Nowak-Sliwinska, Patrycja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435198/
https://www.ncbi.nlm.nih.gov/pubmed/32439932
http://dx.doi.org/10.1038/s41416-020-0890-y
_version_ 1783572290420604928
author Rausch, Magdalena
Weiss, Andrea
Achkhanian, Joanna
Rotari, Andrei
Nowak-Sliwinska, Patrycja
author_facet Rausch, Magdalena
Weiss, Andrea
Achkhanian, Joanna
Rotari, Andrei
Nowak-Sliwinska, Patrycja
author_sort Rausch, Magdalena
collection PubMed
description BACKGROUND: Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. METHODS: We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) method. In a set of genetically distinct human renal cell carcinoma (RCC) cell lines, either treated chronically with sunitinib (−ST) or sunitinib-naive, we identified cell line-specific low-dose-optimised drug combinations (ODC). RESULTS: Six cell-type-specific low-dose drug combinations for three sunitinib-naive as well as three sunitinib pre-treated cells were established. These ODCs effectively inhibited the RCC cell metabolic activity while being ineffective in non-cancerous cells. Based on a single screening test and three searches, starting with ten drugs, we identified highly efficacious drug mixtures containing four drugs. All ODCs contained AZD4547 (FGFR signalling pathway inhibitor) and pictilisib (pan-phosphatidylinositol 3-kinase inhibitor), but varied in the third and fourth drug. ODC treatment significantly decreased cell metabolic activity (up to 70%) and induced apoptosis, independent of the pretreatment with sunitinib. The ODCs outperformed sunitinib, the standard care for RCC. Moreover, short-term starvation potentiated the ODC activity. The translation of the 2D-based results to 3D heterotypic co-culture models revealed significant inhibition of the spheroid growth (up to 95%). CONCLUSION: We demonstrate a promising low-dose drug combination development to obtain drug combinations effective in naive as well as resistant tumours. Nevertheless, we emphasise the need for further mechanistic investigation and preclinical development.
format Online
Article
Text
id pubmed-7435198
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-74351982020-08-27 Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma Rausch, Magdalena Weiss, Andrea Achkhanian, Joanna Rotari, Andrei Nowak-Sliwinska, Patrycja Br J Cancer Article BACKGROUND: Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. METHODS: We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) method. In a set of genetically distinct human renal cell carcinoma (RCC) cell lines, either treated chronically with sunitinib (−ST) or sunitinib-naive, we identified cell line-specific low-dose-optimised drug combinations (ODC). RESULTS: Six cell-type-specific low-dose drug combinations for three sunitinib-naive as well as three sunitinib pre-treated cells were established. These ODCs effectively inhibited the RCC cell metabolic activity while being ineffective in non-cancerous cells. Based on a single screening test and three searches, starting with ten drugs, we identified highly efficacious drug mixtures containing four drugs. All ODCs contained AZD4547 (FGFR signalling pathway inhibitor) and pictilisib (pan-phosphatidylinositol 3-kinase inhibitor), but varied in the third and fourth drug. ODC treatment significantly decreased cell metabolic activity (up to 70%) and induced apoptosis, independent of the pretreatment with sunitinib. The ODCs outperformed sunitinib, the standard care for RCC. Moreover, short-term starvation potentiated the ODC activity. The translation of the 2D-based results to 3D heterotypic co-culture models revealed significant inhibition of the spheroid growth (up to 95%). CONCLUSION: We demonstrate a promising low-dose drug combination development to obtain drug combinations effective in naive as well as resistant tumours. Nevertheless, we emphasise the need for further mechanistic investigation and preclinical development. Nature Publishing Group UK 2020-05-22 2020-08-18 /pmc/articles/PMC7435198/ /pubmed/32439932 http://dx.doi.org/10.1038/s41416-020-0890-y Text en © The Author(s) 2020 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Rausch, Magdalena
Weiss, Andrea
Achkhanian, Joanna
Rotari, Andrei
Nowak-Sliwinska, Patrycja
Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
title Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
title_full Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
title_fullStr Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
title_full_unstemmed Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
title_short Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
title_sort identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435198/
https://www.ncbi.nlm.nih.gov/pubmed/32439932
http://dx.doi.org/10.1038/s41416-020-0890-y
work_keys_str_mv AT rauschmagdalena identificationoflowdosemultidrugcombinationsforsunitinibnaiveandpretreatedrenalcellcarcinoma
AT weissandrea identificationoflowdosemultidrugcombinationsforsunitinibnaiveandpretreatedrenalcellcarcinoma
AT achkhanianjoanna identificationoflowdosemultidrugcombinationsforsunitinibnaiveandpretreatedrenalcellcarcinoma
AT rotariandrei identificationoflowdosemultidrugcombinationsforsunitinibnaiveandpretreatedrenalcellcarcinoma
AT nowaksliwinskapatrycja identificationoflowdosemultidrugcombinationsforsunitinibnaiveandpretreatedrenalcellcarcinoma