Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies

Ekaterina Lesovaya, Alex Yemelyanov, Kirill Kirsanov, Alexander Popa, Gennady Belitsky, Marianna Yakubovskaya, Leo I Gordon, Steven T. Rosen, Irina Budunova*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Glucocorticoids are widely used for the treatment of hematological malignancies; however, their chronic use results in numerous metabolic side effects. Thus, the development of selective glucocorticoid receptor (GR) activators (SEGRA) with improved therapeutic index is important. GR regulates gene expression via (1) transactivation that requires GR homodimer binding to gene promoters and is linked to side effects and (2) transrepression-mediated via negative GR interaction with other transcription factors. Novel GR modulator Compound A (CpdA) prevents GR dimerization, retains glucocorticoid anti-inflammatory activity and has fewer side effects compared with glucocorticoids in vivo. Here we tested CpdA anticancer activity in human T- and B-lymphoma and multiple myeloma cells expressing GR and their counterparts with silenced GR. We found that CpdA in GR-dependent manner strongly inhibited growth and viability of human T-, B-lymphoma and multiple myeloma cells. Furthermore, primary leukemia cell cultures from T-ALL patients appeared to be equally sensitive to glucocorticoid dexamethasone and CpdA. It is known that GR expression is controlled by proteasome. We showed that pretreatment of lymphoma CEM and NCEB cells with proteasome-inhibitor Bortezomib resulted in GR accumulation and enhanced ligand properties of CpdA, shifting GR activity toward transrepression evaluated by inhibition of NFκB and AP-1 transcription factors. We also revealed remarkable GR-dependent cooperation between CpdA and Bortezomib in suppressing growth and survival of T- and B-lymphoma and multiple myeloma MM.1S cells. Overall, our data provide the rationale for novel GR-based therapy for hematological malignancies based on combination of SEGRA with proteasome inhibitors.

Original languageEnglish (US)
Pages (from-to)133-144
Number of pages12
JournalCell Cycle
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2013

Fingerprint

Proteasome Inhibitors
Glucocorticoid Receptors
Hematologic Neoplasms
Drug Therapy
Glucocorticoids
Lymphoma
Multiple Myeloma
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Primary Cell Culture
Transcription Factor AP-1
Dimerization
Proteasome Endopeptidase Complex
Growth
Human Activities
Dexamethasone
Transcriptional Activation

Keywords

  • Glucocorticoid receptor
  • Leukemia
  • Lymphoma
  • Multiple myeloma
  • Proteasome inhibitor
  • Selective GR activator (SEGRA)

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Lesovaya, Ekaterina ; Yemelyanov, Alex ; Kirsanov, Kirill ; Popa, Alexander ; Belitsky, Gennady ; Yakubovskaya, Marianna ; Gordon, Leo I ; Rosen, Steven T. ; Budunova, Irina. / Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies. In: Cell Cycle. 2013 ; Vol. 12, No. 1. pp. 133-144.
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Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies. / Lesovaya, Ekaterina; Yemelyanov, Alex; Kirsanov, Kirill; Popa, Alexander; Belitsky, Gennady; Yakubovskaya, Marianna; Gordon, Leo I; Rosen, Steven T.; Budunova, Irina.

In: Cell Cycle, Vol. 12, No. 1, 01.01.2013, p. 133-144.

Research output: Contribution to journalArticle

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T1 - Combination of a selective activator of the glucocorticoid receptor Compound A with a proteasome inhibitor as a novel strategy for chemotherapy of hematologic malignancies

AU - Lesovaya, Ekaterina

AU - Yemelyanov, Alex

AU - Kirsanov, Kirill

AU - Popa, Alexander

AU - Belitsky, Gennady

AU - Yakubovskaya, Marianna

AU - Gordon, Leo I

AU - Rosen, Steven T.

AU - Budunova, Irina

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Glucocorticoids are widely used for the treatment of hematological malignancies; however, their chronic use results in numerous metabolic side effects. Thus, the development of selective glucocorticoid receptor (GR) activators (SEGRA) with improved therapeutic index is important. GR regulates gene expression via (1) transactivation that requires GR homodimer binding to gene promoters and is linked to side effects and (2) transrepression-mediated via negative GR interaction with other transcription factors. Novel GR modulator Compound A (CpdA) prevents GR dimerization, retains glucocorticoid anti-inflammatory activity and has fewer side effects compared with glucocorticoids in vivo. Here we tested CpdA anticancer activity in human T- and B-lymphoma and multiple myeloma cells expressing GR and their counterparts with silenced GR. We found that CpdA in GR-dependent manner strongly inhibited growth and viability of human T-, B-lymphoma and multiple myeloma cells. Furthermore, primary leukemia cell cultures from T-ALL patients appeared to be equally sensitive to glucocorticoid dexamethasone and CpdA. It is known that GR expression is controlled by proteasome. We showed that pretreatment of lymphoma CEM and NCEB cells with proteasome-inhibitor Bortezomib resulted in GR accumulation and enhanced ligand properties of CpdA, shifting GR activity toward transrepression evaluated by inhibition of NFκB and AP-1 transcription factors. We also revealed remarkable GR-dependent cooperation between CpdA and Bortezomib in suppressing growth and survival of T- and B-lymphoma and multiple myeloma MM.1S cells. Overall, our data provide the rationale for novel GR-based therapy for hematological malignancies based on combination of SEGRA with proteasome inhibitors.

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