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Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases
The DNA repair protein O (6)-methylguanine-DNA-methyltransferase (MGMT) is a key determinant of cancer resistance. The MGMT inhibitors O (6)-benzylguanine (O(6)BG) and O (6)-(4-bromothenyl)guanine (O(6)BTG) failed to enhance the therapeutic response due to toxic side effects when applied in combinat...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655675/ https://www.ncbi.nlm.nih.gov/pubmed/29066805 http://dx.doi.org/10.1038/s41598-017-14129-x |
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author | Tomaszowski, Karl-Heinz Hellmann, Nadja Ponath, Viviane Takatsu, Hiroyuki Shin, Hye-Won Kaina, Bernd |
author_facet | Tomaszowski, Karl-Heinz Hellmann, Nadja Ponath, Viviane Takatsu, Hiroyuki Shin, Hye-Won Kaina, Bernd |
author_sort | Tomaszowski, Karl-Heinz |
collection | PubMed |
description | The DNA repair protein O (6)-methylguanine-DNA-methyltransferase (MGMT) is a key determinant of cancer resistance. The MGMT inhibitors O (6)-benzylguanine (O(6)BG) and O (6)-(4-bromothenyl)guanine (O(6)BTG) failed to enhance the therapeutic response due to toxic side effects when applied in combination with alkylating chemotherapeutics, indicating a need of inhibitor targeting. We assessed MGMT targeting that relies on conjugating the inhibitors O(6)BG and O(6)BTG to ß-D-glucose, resulting in O(6)BG-Glu and O(6)BTG-Glu, respectively. This targeting strategy was selected by taking advantage of high demand of glucose in cancers. Contrary to our expectation, the uptake of O(6)BG-Glu and O(6)BTG-Glu was not dependent on glucose transporters. Instead, it seems that after membrane binding the conjugates are taken up via flippases, which normally transport phospholipids. This membrane binding is the consequence of the amphiphilic character of the conjugates, which at higher concentrations lead to the formation of micelle-like particles in aqueous solution. The unusual uptake mechanism of the conjugates highlights the importance of proper linker selection for a successful ligand-based drug delivery strategy. We also demonstrate that proteins of the P4-Type ATPase family are involved in the transport of the glucose conjugates. The findings are not only important for MGMT inhibitor targeting, but also for other amphiphilic drugs. |
format | Online Article Text |
id | pubmed-5655675 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56556752017-10-31 Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases Tomaszowski, Karl-Heinz Hellmann, Nadja Ponath, Viviane Takatsu, Hiroyuki Shin, Hye-Won Kaina, Bernd Sci Rep Article The DNA repair protein O (6)-methylguanine-DNA-methyltransferase (MGMT) is a key determinant of cancer resistance. The MGMT inhibitors O (6)-benzylguanine (O(6)BG) and O (6)-(4-bromothenyl)guanine (O(6)BTG) failed to enhance the therapeutic response due to toxic side effects when applied in combination with alkylating chemotherapeutics, indicating a need of inhibitor targeting. We assessed MGMT targeting that relies on conjugating the inhibitors O(6)BG and O(6)BTG to ß-D-glucose, resulting in O(6)BG-Glu and O(6)BTG-Glu, respectively. This targeting strategy was selected by taking advantage of high demand of glucose in cancers. Contrary to our expectation, the uptake of O(6)BG-Glu and O(6)BTG-Glu was not dependent on glucose transporters. Instead, it seems that after membrane binding the conjugates are taken up via flippases, which normally transport phospholipids. This membrane binding is the consequence of the amphiphilic character of the conjugates, which at higher concentrations lead to the formation of micelle-like particles in aqueous solution. The unusual uptake mechanism of the conjugates highlights the importance of proper linker selection for a successful ligand-based drug delivery strategy. We also demonstrate that proteins of the P4-Type ATPase family are involved in the transport of the glucose conjugates. The findings are not only important for MGMT inhibitor targeting, but also for other amphiphilic drugs. Nature Publishing Group UK 2017-10-24 /pmc/articles/PMC5655675/ /pubmed/29066805 http://dx.doi.org/10.1038/s41598-017-14129-x Text en © The Author(s) 2017 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/. |
spellingShingle | Article Tomaszowski, Karl-Heinz Hellmann, Nadja Ponath, Viviane Takatsu, Hiroyuki Shin, Hye-Won Kaina, Bernd Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases |
title | Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases |
title_full | Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases |
title_fullStr | Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases |
title_full_unstemmed | Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases |
title_short | Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases |
title_sort | uptake of glucose-conjugated mgmt inhibitors in cancer cells: role of flippases and type iv p-type atpases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5655675/ https://www.ncbi.nlm.nih.gov/pubmed/29066805 http://dx.doi.org/10.1038/s41598-017-14129-x |
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