title: Antitumor effect of non-steroid glucocorticoid receptor ligand CpdA on leukemia cell lines CEM and K562.
abstract: Glucocorticoids (GCs) are widely used in chemotherapy of hematological malignancies, particularly leukemia. Their effect is mediated by glucocorticoid receptor (GR), a well-known transcription factor. Besides their therapeutic impact, GCs may cause a number of side effects leading to various metabolic complications. The goal of immediate interest is testing glucocorticoid analogs capable of induction/enhancement of GR transrepression, but preventing GR dimerization and transactivation leading to side effects. In this work we have investigated effects of a promising new selective GR agonist, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (CpdA), on CEM and K562 leukemia cells. Both cell lines express functional GR. CpdA compared with the glucocorticoid fluocinolone acetonide (FA) exerted more prominent cytostatic and apoptotic effects on the cells. Both cell lines exhibited sensitivity to CpdA, demonstrating a good correlation with the effects of FA on cell growth and viability. In contrast to FA, CpdA did not induce GR transactivation evaluated by no obvious increase in expression of GR target (and dependent) gene FKBP51. At the same time, luciferase assay showed that CpdA efficiently activated transrepression of NF-κB and AP-1 factors. We also evaluated the effect of combined action of CpdA and the proteasome inhibitor Bortezomib. The latter induced a caspase-dependent apoptosis in both T-cell leukemia cell lines. By treatment of CEM cells with different CpdA/GC and Bortezomib doses, we have designed a protocol where CpdA shows potentiating effect on Bortezomib cytotoxic activity. Generally, the present work characterizes a novel non-steroid GR ligand, CpdA, as a promising compound for possible application in leukemia chemotherapy.
authors: Institute of Carcinogenesis, Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia. lesovenok@yandex.ru
authors: E A
authors: EA
authors: Lesovaya
authors: A Yu
authors: AY
authors: Yemelyanov
authors: K I
authors: KI
authors: Kirsanov
authors: M G
authors: MG
authors: Yakubovskaya
authors: I V
authors: IV
authors: Budunova
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D054697:Cytostatic Agents / Q000494:pharmacology*; D005446:Fluocinolone Acetonide / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism*; D008024:Ligands; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014439:Tyramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000085:Acetates; D001897:Boronic Acids; D000069286:Bortezomib; D054697:Cytostatic Agents; D005446:Fluocinolone Acetonide; D008024:Ligands; D016328:NF-kappa B; D011719:Pyrazines; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D018808:Transcription Factor AP-1; D014439:Tyramine; D000099159:Tacrolimus Binding Protein 5; C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine