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Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects
AIMS: This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) pat...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299784/ https://www.ncbi.nlm.nih.gov/pubmed/34599518 http://dx.doi.org/10.1111/bcp.15098 |
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author | Vasilogianni, Areti‐Maria Al‐Majdoub, Zubida M. Achour, Brahim Peters, Sheila Annie Rostami‐Hodjegan, Amin Barber, Jill |
author_facet | Vasilogianni, Areti‐Maria Al‐Majdoub, Zubida M. Achour, Brahim Peters, Sheila Annie Rostami‐Hodjegan, Amin Barber, Jill |
author_sort | Vasilogianni, Areti‐Maria |
collection | PubMed |
description | AIMS: This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. METHODS: Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics. RESULTS: Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54‐fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13‐fold) drug clearance when using cancer‐specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76‐fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over‐expression of such pathways. CONCLUSION: This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population‐specific abundance data in PBPK models for cancer. |
format | Online Article Text |
id | pubmed-9299784 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92997842022-07-21 Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects Vasilogianni, Areti‐Maria Al‐Majdoub, Zubida M. Achour, Brahim Peters, Sheila Annie Rostami‐Hodjegan, Amin Barber, Jill Br J Clin Pharmacol Original Articles AIMS: This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. METHODS: Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics. RESULTS: Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54‐fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13‐fold) drug clearance when using cancer‐specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76‐fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over‐expression of such pathways. CONCLUSION: This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population‐specific abundance data in PBPK models for cancer. John Wiley and Sons Inc. 2021-12-03 2022-04 /pmc/articles/PMC9299784/ /pubmed/34599518 http://dx.doi.org/10.1111/bcp.15098 Text en © 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Vasilogianni, Areti‐Maria Al‐Majdoub, Zubida M. Achour, Brahim Peters, Sheila Annie Rostami‐Hodjegan, Amin Barber, Jill Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects |
title | Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects |
title_full | Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects |
title_fullStr | Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects |
title_full_unstemmed | Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects |
title_short | Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects |
title_sort | proteomics of colorectal cancer liver metastasis: a quantitative focus on drug elimination and pharmacodynamics effects |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9299784/ https://www.ncbi.nlm.nih.gov/pubmed/34599518 http://dx.doi.org/10.1111/bcp.15098 |
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