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Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies

Dorien Clarisse (UGent) , Karlien Van Wesemael (UGent) , Jan Tavernier (UGent) , Fritz Offner (UGent) , Ilse Beck (UGent) and Karolien De Bosscher (UGent)
(2018) PLOS ONE. 13(5).
Author
Organization
Abstract
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.
Keywords
PROSTATE-CANCER CELLS, INDUCED APOPTOSIS, MOLECULAR-MECHANISMS, MEDIATED, APOPTOSIS, PLANT-ORIGIN, MOUSE MODEL, IN-VIVO, KAPPA-B, RESISTANCE, LIGAND

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Citation

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MLA
Clarisse, Dorien et al. “Effect of Combining Glucocorticoids with Compound A on Glucocorticoid Receptor Responsiveness in Lymphoid Malignancies.” PLOS ONE 13.5 (2018): n. pag. Print.
APA
Clarisse, D., Van Wesemael, K., Tavernier, J., Offner, F., Beck, I., & De Bosscher, K. (2018). Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. PLOS ONE, 13(5).
Chicago author-date
Clarisse, Dorien, Karlien Van Wesemael, Jan Tavernier, Fritz Offner, Ilse Beck, and Karolien De Bosscher. 2018. “Effect of Combining Glucocorticoids with Compound A on Glucocorticoid Receptor Responsiveness in Lymphoid Malignancies.” Plos One 13 (5).
Chicago author-date (all authors)
Clarisse, Dorien, Karlien Van Wesemael, Jan Tavernier, Fritz Offner, Ilse Beck, and Karolien De Bosscher. 2018. “Effect of Combining Glucocorticoids with Compound A on Glucocorticoid Receptor Responsiveness in Lymphoid Malignancies.” Plos One 13 (5).
Vancouver
1.
Clarisse D, Van Wesemael K, Tavernier J, Offner F, Beck I, De Bosscher K. Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies. PLOS ONE. 2018;13(5).
IEEE
[1]
D. Clarisse, K. Van Wesemael, J. Tavernier, F. Offner, I. Beck, and K. De Bosscher, “Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies,” PLOS ONE, vol. 13, no. 5, 2018.
@article{8563262,
  abstract     = {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.},
  articleno    = {e0197000},
  author       = {Clarisse, Dorien and Van Wesemael, Karlien and Tavernier, Jan and Offner, Fritz and Beck, Ilse and De Bosscher, Karolien},
  issn         = {1932-6203},
  journal      = {PLOS ONE},
  keywords     = {PROSTATE-CANCER CELLS,INDUCED APOPTOSIS,MOLECULAR-MECHANISMS,MEDIATED,APOPTOSIS,PLANT-ORIGIN,MOUSE MODEL,IN-VIVO,KAPPA-B,RESISTANCE,LIGAND},
  language     = {eng},
  number       = {5},
  pages        = {17},
  title        = {Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies},
  url          = {http://dx.doi.org/10.1371/journal.pone.0197000},
  volume       = {13},
  year         = {2018},
}

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