Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

Sundahl, Nora; Clarisse, Dorien; Bracke, Marc; Offner, Fritz; Berghe, Wim Vanden; Beck, Ilse

doi:10.18632/oncoscience.315

Cited by 26 publications

(19 citation statements)

References 150 publications

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“…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 ].…”

Section: Introductionmentioning

confidence: 99%

“…CpdA has been successfully applied in vivo improving the disease parameters in mouse models of different inflammatory disorders [ 27 , 30 – 35 ]. CpdA was also shown to have anti-cancer properties, as it induced apoptosis in prostate, bladder, leukemia and multiple myeloma cells [ 4 , 28 , 36 – 39 ]. Recently, our group demonstrated in A549 cells that CpdA could modulate Dex-bound GR by enhancing both anti-inflammatory GRE-driven gene expression and the suppression of pro-inflammatory gene expression [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…However, the potential limitations of using GCs for cancer therapy are their side effects such as hyperglycemia and immunosuppression. One approach to avoid such potential problems is to develop selective glucocorticoid receptor agonists and modulators (SEGRAM) ( Sundahl et al ., 2016 ). GCs inhibit NRF2 through the protein-protein interaction between GCR and NRF2, but not through the regulation of transcriptional activity of GCR which is responsible for the effects on metabolism and immune function; therefore, it would be possible to design a GC analog that binds to GCR only to induce the interaction with NRF2 and GSK3, but not sufficient to induce its transcriptional activity ( Fig.…”

Section: Future Directionsmentioning

confidence: 99%

Dysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities

Jung

Yoo

Shin

et al. 2018

Biomolecules & Therapeutics

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Nuclear factor E2-related factor 2 (NRF2) plays an important role in redox metabolism and antioxidant defense. Under normal conditions, NRF2 proteins are maintained at very low levels because of their ubiquitination and proteasomal degradation via binding to the kelch-like ECH associated protein 1 (KEAP1)-E3 ubiquitin ligase complex. However, oxidative and/or electrophilic stresses disrupt the KEAP1-NRF2 interaction, which leads to the accumulation and transactivation of NRF2. During recent decades, a growing body of evidence suggests that NRF2 is frequently activated in many types of cancer by multiple mechanisms, including the genetic mutations in the KEAP1-NRF2 pathway. This suggested that NRF2 inhibition is a promising strategy for cancer therapy. Recently, several NRF2 inhibitors have been reported with anti-tumor efficacy. Here, we review the mechanisms whereby NRF2 is dysregulated in cancer and its contribution to the tumor development and radiochemoresistance. In addition, among the NRF2 inhibitors reported so far, we summarize and discuss repurposed NRF2 inhibitors with their potential mechanisms and provide new insights to develop selective NRF2 inhibitors.

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“…Synthetic glucocorticoids, such as dexamethasone are commonly used in tumor therapy ( 6 ). However, recent data have indicated that mortality is increased in patients with TNBC variants overexpressing glucocorticoid receptor (GR).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor overexpression slightly shifts microRNA expression patterns in triple-negative breast cancer

et al. 2018

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Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with limited options for clinical intervention. As with many solid tumors, TNBC is known to promote invasiveness and metastasis by secreting extracellular vesicles (EVs) capable of modulating the behaviour of recipient cells. Recent investigations have demonstrated that high expression levels of glucocorticoid receptor (GR) in TNBC are linked to therapy resistance, higher recurrence rates and increased mortality. In addition to activating protein-coding genes, GR is also involved in the expression of short non-coding RNAs including microRNAs (miRNAs or miRs). The molecular mechanisms responsible for the oncogenic effects of GR on TNBC have yet to be fully elucidated; however, emerging evidence suggests that miRNAs may play a pivotal role in tumorigenesis and metastasis. Thus, the aim of this study was to identify GR-regulated cellular and vesicular miRNAs that might contribute to the particularly oncogenic phenotype of TNBC with a high GR expression. We analyzed miRNA profiles of three TNBC cell lines using an in vitro model of GR overexpression. Next-generation sequencing revealed minor, cell line-specific changes in cellular miRNA expression, whereas vesicular miRNAs were not significantly regulated by GR. Additionally, the analysis of predicted miRNA targets failed to establish a causal link between GR-induced miRNA expression and oncogenic signaling. On the whole, given that GR influences miRNA profiles to only a small degree, other mechanisms are more likely to be responsible for the increased mortality of patients with TNBC with a high GR expression.

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Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

Cited by 26 publications

References 150 publications

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

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

Dysregulation of NRF2 in Cancer: from Molecular Mechanisms to Therapeutic Opportunities

Glucocorticoid receptor overexpression slightly shifts microRNA expression patterns in triple-negative breast cancer

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