Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies.
Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5940183?pdf=render |
| _version_ | 1818248572053749760 |
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| author | Dorien Clarisse Karlien Van Wesemael Jan Tavernier Fritz Offner Ilse M Beck Karolien De Bosscher |
| author_facet | Dorien Clarisse Karlien Van Wesemael Jan Tavernier Fritz Offner Ilse M Beck Karolien De Bosscher |
| author_sort | Dorien Clarisse |
| collection | DOAJ |
| description | Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does not support GR-mediated transactivation. Here, we examined whether the combination of CpdA with the classic GC dexamethasone (Dex) may improve GC responsiveness of MM and ALL cell lines. We find that the combination of Dex and CpdA does not substantially enhance GC-mediated cell killing. In line, several apoptosis hallmarks, such as caspase 3/7 activity, PARP cleavage and the levels of cleaved-caspase 3 remain unchanged upon combining Dex with CpdA. Moreover, we monitor no additional inhibition of cell proliferation and the homologous downregulation of GR is not counteracted by the combination of Dex and CpdA. In addition, CpdA is unable to modulate Dex-liganded GR transactivation and transrepression, yet, Dex-mediated transrepression is also aberrant in these lymphoid cell lines. Together, transrepression-favoring compounds, alone or combined with GCs, do not seem a valid strategy in the treatment of lymphoid malignancies. |
| first_indexed | 2024-12-12T15:22:43Z |
| format | Article |
| id | doaj.art-324635f5e56c4638ba365ff33716d759 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T15:22:43Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-324635f5e56c4638ba365ff33716d7592022-12-22T00:20:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01135e019700010.1371/journal.pone.0197000Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies.Dorien ClarisseKarlien Van WesemaelJan TavernierFritz OffnerIlse M BeckKarolien De BosscherGlucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does not support GR-mediated transactivation. Here, we examined whether the combination of CpdA with the classic GC dexamethasone (Dex) may improve GC responsiveness of MM and ALL cell lines. We find that the combination of Dex and CpdA does not substantially enhance GC-mediated cell killing. In line, several apoptosis hallmarks, such as caspase 3/7 activity, PARP cleavage and the levels of cleaved-caspase 3 remain unchanged upon combining Dex with CpdA. Moreover, we monitor no additional inhibition of cell proliferation and the homologous downregulation of GR is not counteracted by the combination of Dex and CpdA. In addition, CpdA is unable to modulate Dex-liganded GR transactivation and transrepression, yet, Dex-mediated transrepression is also aberrant in these lymphoid cell lines. Together, transrepression-favoring compounds, alone or combined with GCs, do not seem a valid strategy in the treatment of lymphoid malignancies.http://europepmc.org/articles/PMC5940183?pdf=render |
| spellingShingle | Dorien Clarisse Karlien Van Wesemael Jan Tavernier Fritz Offner Ilse M Beck Karolien De Bosscher Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. PLoS ONE |
| title | Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. |
| title_full | Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. |
| title_fullStr | Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. |
| title_full_unstemmed | Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. |
| title_short | Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. |
| title_sort | effect of combining glucocorticoids with compound a on glucocorticoid receptor responsiveness in lymphoid malignancies |
| url | http://europepmc.org/articles/PMC5940183?pdf=render |
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