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

Date Published: May 8, 2018

Publisher: Public Library of Science

Author(s): Dorien Clarisse, Karlien Van Wesemael, Jan Tavernier, Fritz Offner, Ilse M. Beck, Karolien De Bosscher, Arun Rishi.

http://doi.org/10.1371/journal.pone.0197000

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.

Partial Text

Endogenous glucocorticoids (GCs), e.g. cortisol in humans, are stress-stimulated steroidal hormones that modulate metabolism, inflammation, development, reproduction and the immune system [1,2]. Therapeutically, exogenous GCs, e.g. dexamethasone (Dex), are mostly used to treat inflammatory disorders such as rheumatoid arthritis, inflammatory bowel disease, asthma and atopic dermatitis [3]. In addition, GCs are deployed in cancer, either as adjuvant (e.g. breast cancer) or as anti-cancer therapy (e.g. multiple myeloma) [4]. As co-medication, GCs reduce edema, nausea and vomiting, avoid uncontrolled immune reactions caused by chemotherapeutics and alleviate pain [5]. In lymphoid malignancies, such as multiple myeloma (MM) [6] and acute lymphoblastic leukemia (ALL) [7], GCs induce apoptosis of the malignant cells [5,8].

The potential of SEGRAMs to reduce the number and intensity of GC-coupled side effects with improved therapeutic efficacy and prolonged responsiveness [3,15], is an attractive route to explore in lymphoid malignancies. Therefore, we investigated whether the combination of classic GCs with transrepression-favoring SEGRAMs could promote GC-induced apoptosis and/or postpone GC resistance by protecting GR from degradation.

 

Source:

http://doi.org/10.1371/journal.pone.0197000