title: PXD101 potentiates hormonal therapy and prevents the onset of castration-resistant phenotype modulating androgen receptor, HSP90, and CRM1 in preclinical models of prostate cancer.
abstract: Aberrant activation or 'reactivation' of androgen receptor (AR) during androgen ablation therapy shows a potential cause for the development of castration-resistant prostate cancer. This study tested the hypothesis that PXD101, a potent pan histone deacetylase (HDAC) inhibitor, may prevent onset of castration-resistant phenotype and potentiate hormonal therapy. A panel of human prostate cancer cells with graded castration-resistant phenotype and in vivo models were used to verify this hypothesis. In this report, we demonstrated that hormonal manipulation favors the onset of castration-resistant phenotype increasing HDAC expression and activity as well as modulating expression and activity of AR, EGFR, HER2, and Akt. Consistent with these observations, the functional knockdown of HDACs by PXD101 prevented the onset of castration-resistant phenotype with a significant downregulation of AR, EGFR, HER2, and Akt expression/activity. The dysregulation of functional cooperation between HDAC6 with hsp90, on the one hand, and between GSK-3β with CRM1, on the other hand, may explain the biological effects of PXD101. In this regard, the HDAC6 silencing or the functional knockdown of hsp90 by 17AAG resulted in the selective downregulation of AR, EGFR, HER2, and Akt expression/activity, while the decreased phosphorylation of GSK-3β mediated by PXD101 increased the nuclear expression of CRM1, which in turn modified the AR and survivin recycling with increased caspase 3 activity. HDAC inhibitors retain the ability to prevent the onset of castration-resistant phenotype and, therefore, merit clinical investigation in this setting. However, additional data are needed to develop clinical treatment strategies for this disease stage.
authors.affiliation: Laboratory of Radiobiology, Department of Experimental Medicine, University of L'Aquila, Via Vetoio, Coppito-2, 67100 L'Aquila, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.forename: Francesco
authors.initials: F
authors.lastname: Marampon
authors.forename: Paola
authors.initials: P
authors.lastname: Muzi
authors.forename: Andrea
authors.initials: A
authors.lastname: Mancini
authors.forename: Margherita
authors.initials: M
authors.lastname: Piccolella
authors.forename: Paola
authors.initials: P
authors.lastname: Negri-Cesi
authors.forename: Marcella
authors.initials: M
authors.lastname: Motta
authors.forename: Andrea
authors.initials: A
authors.lastname: Lenzi
authors.forename: Ernesto
authors.initials: E
authors.lastname: Di Cesare
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tombolini
authors.forename: Emmanuele A
authors.initials: EA
authors.lastname: Jannini
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002369:Castration; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D028884:Karyopherins / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000494:pharmacology; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000494:pharmacology; D000097606:Exportin 1 Protein
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018841:HSP90 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D028884:Karyopherins; D009570:Nitriles; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D014105:Tosyl Compounds; D000097606:Exportin 1 Protein; C410798:AR protein, human; C053541:bicalutamide; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C487081:belinostat
keywords: PXD101; androgen receptor; epigenetic; histone deacetylase; hormone refractory prostate cancer