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Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration

Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-bi...

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Autores principales: Krchniakova, Maria, Skoda, Jan, Neradil, Jakub, Chlapek, Petr, Veselska, Renata
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247577/
https://www.ncbi.nlm.nih.gov/pubmed/32365759
http://dx.doi.org/10.3390/ijms21093157
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author Krchniakova, Maria
Skoda, Jan
Neradil, Jakub
Chlapek, Petr
Veselska, Renata
author_facet Krchniakova, Maria
Skoda, Jan
Neradil, Jakub
Chlapek, Petr
Veselska, Renata
author_sort Krchniakova, Maria
collection PubMed
description Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients.
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spelling pubmed-72475772020-06-10 Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration Krchniakova, Maria Skoda, Jan Neradil, Jakub Chlapek, Petr Veselska, Renata Int J Mol Sci Review Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients. MDPI 2020-04-30 /pmc/articles/PMC7247577/ /pubmed/32365759 http://dx.doi.org/10.3390/ijms21093157 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Krchniakova, Maria
Skoda, Jan
Neradil, Jakub
Chlapek, Petr
Veselska, Renata
Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration
title Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration
title_full Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration
title_fullStr Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration
title_full_unstemmed Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration
title_short Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration
title_sort repurposing tyrosine kinase inhibitors to overcome multidrug resistance in cancer: a focus on transporters and lysosomal sequestration
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247577/
https://www.ncbi.nlm.nih.gov/pubmed/32365759
http://dx.doi.org/10.3390/ijms21093157
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