Cargando…

The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells

BACKGROUND: Glucocorticoids (GCs) cause apoptosis in malignant cells of lymphoid lineage by transcriptionally regulating a plethora of genes. As a result, GCs are included in almost all treatment protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (chALL). The mo...

Descripción completa

Detalles Bibliográficos
Autores principales: Bindreither, Daniel, Ecker, Simone, Gschirr, Barbara, Kofler, Anita, Kofler, Reinhard, Rainer, Johannes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133055/
https://www.ncbi.nlm.nih.gov/pubmed/25103118
http://dx.doi.org/10.1186/1471-2164-15-662
_version_ 1782330711198400512
author Bindreither, Daniel
Ecker, Simone
Gschirr, Barbara
Kofler, Anita
Kofler, Reinhard
Rainer, Johannes
author_facet Bindreither, Daniel
Ecker, Simone
Gschirr, Barbara
Kofler, Anita
Kofler, Reinhard
Rainer, Johannes
author_sort Bindreither, Daniel
collection PubMed
description BACKGROUND: Glucocorticoids (GCs) cause apoptosis in malignant cells of lymphoid lineage by transcriptionally regulating a plethora of genes. As a result, GCs are included in almost all treatment protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (chALL). The most commonly used synthetic GCs in the clinical setting are prednisolone and dexamethasone. While the latter has a higher activity and more effectively reduces the tumor load in patients, it is also accompanied by more serious adverse effects than the former. Whether this difference might be explained by regulation of different genes by the two GCs has never been addressed. RESULTS: Using a recently developed GC bioassay based on a GC-responsive reporter construct in human Jurkat T-ALL cells, we found ~7-fold higher biological activity with dexamethasone than prednisolone. Similarly, 1.0e-7 M dexamethasone and 7.0e-7 M prednisolone triggered similar cell death rates in CCRF-CEM-C7H2 T-chALL cells after 72 hours of treatment. Using microarray-based whole genome expression profiling and a variety of statistical and other approaches, we compared the transcriptional response of chALL cells to 6 hour exposure to both synthetic GCs at the above concentrations. Our experiments did not detect any gene whose regulation by dexamethasone differed significantly from that by prednisolone. CONCLUSIONS: Our findings suggest that the reported differences in treatment efficacy and cytotoxicity of dexamethasone and prednisolone are not caused by inherent differences of the 2 drugs to regulate the expression of certain genes, but rather result either from applying them in biologically in-equivalent concentrations and/or from differences in their pharmacokinetics and - dynamics resulting in different bioactivities in tumor cells and normal tissues. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-662) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4133055
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-41330552014-08-18 The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells Bindreither, Daniel Ecker, Simone Gschirr, Barbara Kofler, Anita Kofler, Reinhard Rainer, Johannes BMC Genomics Research Article BACKGROUND: Glucocorticoids (GCs) cause apoptosis in malignant cells of lymphoid lineage by transcriptionally regulating a plethora of genes. As a result, GCs are included in almost all treatment protocols for lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (chALL). The most commonly used synthetic GCs in the clinical setting are prednisolone and dexamethasone. While the latter has a higher activity and more effectively reduces the tumor load in patients, it is also accompanied by more serious adverse effects than the former. Whether this difference might be explained by regulation of different genes by the two GCs has never been addressed. RESULTS: Using a recently developed GC bioassay based on a GC-responsive reporter construct in human Jurkat T-ALL cells, we found ~7-fold higher biological activity with dexamethasone than prednisolone. Similarly, 1.0e-7 M dexamethasone and 7.0e-7 M prednisolone triggered similar cell death rates in CCRF-CEM-C7H2 T-chALL cells after 72 hours of treatment. Using microarray-based whole genome expression profiling and a variety of statistical and other approaches, we compared the transcriptional response of chALL cells to 6 hour exposure to both synthetic GCs at the above concentrations. Our experiments did not detect any gene whose regulation by dexamethasone differed significantly from that by prednisolone. CONCLUSIONS: Our findings suggest that the reported differences in treatment efficacy and cytotoxicity of dexamethasone and prednisolone are not caused by inherent differences of the 2 drugs to regulate the expression of certain genes, but rather result either from applying them in biologically in-equivalent concentrations and/or from differences in their pharmacokinetics and - dynamics resulting in different bioactivities in tumor cells and normal tissues. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2164-15-662) contains supplementary material, which is available to authorized users. BioMed Central 2014-08-07 /pmc/articles/PMC4133055/ /pubmed/25103118 http://dx.doi.org/10.1186/1471-2164-15-662 Text en © Bindreither et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Bindreither, Daniel
Ecker, Simone
Gschirr, Barbara
Kofler, Anita
Kofler, Reinhard
Rainer, Johannes
The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells
title The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells
title_full The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells
title_fullStr The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells
title_full_unstemmed The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells
title_short The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells
title_sort synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133055/
https://www.ncbi.nlm.nih.gov/pubmed/25103118
http://dx.doi.org/10.1186/1471-2164-15-662
work_keys_str_mv AT bindreitherdaniel thesyntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT eckersimone thesyntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT gschirrbarbara thesyntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT kofleranita thesyntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT koflerreinhard thesyntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT rainerjohannes thesyntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT bindreitherdaniel syntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT eckersimone syntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT gschirrbarbara syntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT kofleranita syntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT koflerreinhard syntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells
AT rainerjohannes syntheticglucocorticoidsprednisoloneanddexamethasoneregulatethesamegenesinacutelymphoblasticleukemiacells