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

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 NFкB 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.

Keywords: :

• glucocorticoid receptor
• selective GR activator (SEGRA)
• lymphoma
• leukemia
• multiple myeloma
• proteasome inhibitor

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

We are grateful to Dr. O. Volpert (Northwestern University) for fruitful discussion of our work. We thank SDRC DNA/RNA delivery Core and RHLCCC Flow Cytometry Core Facility for technical support. Work is supported by grants: RO1CA118890, SPORE in Prostate Cancer, P30 CA090386, Northwestern University RHLCCC (to I.B.), ACS IL #160185 (to A.Y.), RFBR # 10–04–00979 (to M.Y.), UICC ICRETT-09–137 (to E.L.), EACR Travel Fellowship Award (to E.L.), RFBR grant 12–04–31148 (to E.L.).

Author Notes

E.L. designed and performed research, analyzed and interpreted data, prepared figures; A.Y. designed and performed research, analyzed and interpreted data, prepared figures; K.K. performed research, analyzed and interpreted data; A.P. collected data, analyzed and interpreted data; G.B. analyzed and interpreted data; M.Y. designed research, analyzed and interpreted data; L.G. analyzed and interpreted data; S.R. analyzed and interpreted data; I.B. designed research, analyzed and interpreted data, wrote the manuscript.