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PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line

PURPOSE: The development of multidrug resistance (MDR) is one of the major limitations in the treatment of cancer. Induction of P-glycoprotein (Pgp) has been regarded as one of the main mechanisms underlying anticancer drug-induced MDR. Since the induction of Pgp is (in part) regulated by the pregna...

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Autores principales: Harmsen, Stefan, Meijerman, I., Febus, C. L., Maas-Bakker, R. F., Beijnen, J. H., Schellens, J. H. M.
Formato: Texto
Lenguaje:English
Publicado: Springer-Verlag 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904455/
https://www.ncbi.nlm.nih.gov/pubmed/20041327
http://dx.doi.org/10.1007/s00280-009-1221-4
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author Harmsen, Stefan
Meijerman, I.
Febus, C. L.
Maas-Bakker, R. F.
Beijnen, J. H.
Schellens, J. H. M.
author_facet Harmsen, Stefan
Meijerman, I.
Febus, C. L.
Maas-Bakker, R. F.
Beijnen, J. H.
Schellens, J. H. M.
author_sort Harmsen, Stefan
collection PubMed
description PURPOSE: The development of multidrug resistance (MDR) is one of the major limitations in the treatment of cancer. Induction of P-glycoprotein (Pgp) has been regarded as one of the main mechanisms underlying anticancer drug-induced MDR. Since the induction of Pgp is (in part) regulated by the pregnane X receptor (PXR), the ability of several widely used anticancer drugs to activate PXR-mediated Pgp induction was investigated. METHODS: A Pgp-reporter gene assay was employed to determine the ability of a panel of widely used anticancer drugs to induce Pgp. To further assess whether PXR could be involved in the induction of Pgp by anticancer drugs, Pgp protein expression after treatment with the anticancer drugs was determined in both wild-type and PXR-knocked down LS180 cells. Furthermore, the effect of the anticancer drugs on the intracellular accumulation of the Pgp-probes rhodamine 123 and doxorubicin was determined. RESULTS: Our study showed that vincristine, tamoxifen, vinblastine, docetaxel, cyclophosphamide, flutamide, ifosfamide and paclitaxel activate PXR-mediated Pgp induction, and were additionally shown to affect the intracellular accumulation of the Pgp probe rhodamine 123. Moreover, PXR activation was also shown to reduce the cytotoxic activity of the Pgp substrate doxorubicin in colon cancer cells. CONCLUSION: Our results indicate that several anticancer drugs can activate PXR-mediated induction of Pgp and affect the accumulation of Pgp substrates.
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spelling pubmed-29044552010-08-06 PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line Harmsen, Stefan Meijerman, I. Febus, C. L. Maas-Bakker, R. F. Beijnen, J. H. Schellens, J. H. M. Cancer Chemother Pharmacol Original Article PURPOSE: The development of multidrug resistance (MDR) is one of the major limitations in the treatment of cancer. Induction of P-glycoprotein (Pgp) has been regarded as one of the main mechanisms underlying anticancer drug-induced MDR. Since the induction of Pgp is (in part) regulated by the pregnane X receptor (PXR), the ability of several widely used anticancer drugs to activate PXR-mediated Pgp induction was investigated. METHODS: A Pgp-reporter gene assay was employed to determine the ability of a panel of widely used anticancer drugs to induce Pgp. To further assess whether PXR could be involved in the induction of Pgp by anticancer drugs, Pgp protein expression after treatment with the anticancer drugs was determined in both wild-type and PXR-knocked down LS180 cells. Furthermore, the effect of the anticancer drugs on the intracellular accumulation of the Pgp-probes rhodamine 123 and doxorubicin was determined. RESULTS: Our study showed that vincristine, tamoxifen, vinblastine, docetaxel, cyclophosphamide, flutamide, ifosfamide and paclitaxel activate PXR-mediated Pgp induction, and were additionally shown to affect the intracellular accumulation of the Pgp probe rhodamine 123. Moreover, PXR activation was also shown to reduce the cytotoxic activity of the Pgp substrate doxorubicin in colon cancer cells. CONCLUSION: Our results indicate that several anticancer drugs can activate PXR-mediated induction of Pgp and affect the accumulation of Pgp substrates. Springer-Verlag 2009-12-30 2010 /pmc/articles/PMC2904455/ /pubmed/20041327 http://dx.doi.org/10.1007/s00280-009-1221-4 Text en © The Author(s) 2009 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Original Article
Harmsen, Stefan
Meijerman, I.
Febus, C. L.
Maas-Bakker, R. F.
Beijnen, J. H.
Schellens, J. H. M.
PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
title PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
title_full PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
title_fullStr PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
title_full_unstemmed PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
title_short PXR-mediated induction of P-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
title_sort pxr-mediated induction of p-glycoprotein by anticancer drugs in a human colon adenocarcinoma-derived cell line
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904455/
https://www.ncbi.nlm.nih.gov/pubmed/20041327
http://dx.doi.org/10.1007/s00280-009-1221-4
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