title: 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.
authors.affiliation: Department of Chemical Carcinogenesis, Institute of Carcinogenesis, Blokhin Cancer Research Center, RAMS, Moscow, Russia.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Lesovaya
authors.forename: Alexander
authors.initials: A
authors.lastname: Yemelyanov
authors.forename: Kirill
authors.initials: K
authors.lastname: Kirsanov
authors.forename: Alexander
authors.initials: A
authors.lastname: Popa
authors.forename: Gennady
authors.initials: G
authors.lastname: Belitsky
authors.forename: Marianna
authors.initials: M
authors.lastname: Yakubovskaya
authors.forename: Leo I
authors.initials: LI
authors.lastname: Gordon
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.forename: Irina
authors.initials: I
authors.lastname: Budunova
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000627:therapeutic use / Q000633:toxicity; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000633:toxicity; D019281:Dimerization; D004357:Drug Synergism; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D061988:Proteasome Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D011719:Pyrazines / Q000627:therapeutic use / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation; D014230:Triazoles / Q000627:therapeutic use / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D014230:Triazoles; C524574:compound A (octyltriazole); D000069286:Bortezomib; D003907:Dexamethasone