title: Differential effects of PXD101 (belinostat) on androgen-dependent and             androgen-independent prostate cancer models.
abstract: Histone deacetylase inhibitors (HDACi) are promising epigenetic cancer chemotherapeutics             rapidly approaching clinical use. In this study, we tested using in vitro and             in vivo models the differential biological effects of a novel HDAC inhibitor [belinostat             (PXD101)], in a wide panel of androgen-sensitive and androgen-independent tumor             cells. Belinostat significantly increased acetylation of histones H3 and H4. Belinostat             potently inhibited the growth of prostate cancer cell lines (IC50 range from 0.5             to 2.5 µM) with cytotoxic activity preferentially against tumor cells. This agent             induced G2/M arrest and increased significantly the percentage of apoptosis mainly             in androgen-sensitive tumor cells confirming its growth-inhibitory effects. The             cell death mechanisms were studied in three different prostate cancer cell lines             with different androgen dependence and expression of androgen receptor; LAPC-4             and 22rv1 (androgen-dependent and expressing androgen receptor) and PC3 (androgen-independent             not expressing androgen receptor). Belinostat induced the expression of p21 and             p27, acetylation of p53 and G2/M arrest associated with Bcl2 and Bcl-Xl downmodulation             and significant reduction of survivin, IAPs and Akt/pAkt and increased caspase-8             and -9 expression/activity. Belinostat effectiveness was dependent on the androgen             receptor (AR), since the stable transfection of AR greatly increased the efficacy             of this HDAC inhibitor. These observations were correlated using in vivo models.             We demonstrated that belinostat preferentially resulted in antitumor effect in             androgen-dependent tumor cells expressing AR. Our findings provide evidence that             belinostat may be a promising anticancer drug for prostate cancer expressing AR,             supporting its clinical role in prostate cancer.
authors: Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy.
authors: Giovanni Luca
authors: GL
authors: Gravina
authors: Francesco
authors: F
authors: Marampon
authors: Ilaria
authors: I
authors: Giusti
authors: Eleonora
authors: E
authors: Carosa
authors: Stefania
authors: S
authors: Di Sante
authors: Enrico
authors: E
authors: Ricevuto
authors: Vincenza
authors: V
authors: Dolo
authors: Vincenzo
authors: V
authors: Tombolini
authors: Emmanuele A
authors: EA
authors: Jannini
authors: Claudio
authors: C
authors: Festuccia
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D013449:Sulfonamides; D014162:Transfection / Q000379:methods; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C410798:AR protein, human; D000728:Androgens; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011944:Receptors, Androgen; D013449:Sulfonamides; C487081:belinostat