OBJECTIVE: Calcitriol analogues might represent an interesting new therapy for benign prostate hyperplasia (BPH). We here report the preclinical characterization of BXL-628, an analogue selected for an ongoing double-blind, randomized, placebo-controlled phase II trial in BPH. DESIGN: Experiments with BXL-628 were carried out in human BPH cells and in the ventral prostate of intact and castrated rats. METHODS: BPH cell and rat prostate growth were evaluated along with morphological and biochemical hallmarks of apoptosis. RESULTS: BXL-628 inhibited human BPH cell proliferation and induced apoptosis even in the presence of androgens or growth factors. It also decreased prostate growth to an extent similar to finasteride, inducing DNA fragmentation and apoptosis, both in intact and in testosterone-supplemented castrated rats. Accordingly, BXL-628, like finasteride, increased the expression of clusterin, a prostatic atrophy marker. However, BXL-628 did not inhibit 5 alpha-reductase 1 and 2, did not bind to the androgen receptor (AR) in BPH homogenates and did not affect AR-coupled luciferase activity. In addition, BXL-628 did not affect rat pituitary and testis activity or calcemia. CONCLUSIONS: BXL-628 inhibited in vitro and in vivo prostate cell proliferation, and therefore might represent a novel, interesting option for the treatment of BPH.
C Crescioli, P Ferruzzi, A Caporali, M Scaltriti, S Bettuzzi, R Mancina, S Gelmini, M Serio, D Villari, GB Vannelli, E Colli, L Adorini and M Maggi
D C Gomes, S A Jamra, L F Leal, L M Colli, M L Campanini, R S Oliveira, C E Martinelli Jr, P C L Elias, A C Moreira, H R Machado, F Saggioro, L Neder, M Castro and S R Antonini
Pituitary stem cells play a role in the oncogenesis of human adamantinomatous craniopharyngiomas (aCPs). We hypothesized that crosstalk between the Wnt/β-catenin and Sonic Hedgehog (SHH) pathways, both of which are important in normal pituitary development, would contribute to the pathogenesis of aCPs.
To explore the mRNA and protein expression of components of the SHH signaling pathway in aCPs and their relationship with the identification of CTNNB1/β-catenin mutations and patients outcomes.
Patients and methods
In 18 aCP samples, CTNNB1 was sequenced, and the mRNA expression levels of SHH pathway members (SHH, PTCH1, SMO, GLI1, GLI2, GLI3, and SUFU) and SMO, GLI1, GLI3, SUFU, β-catenin, and Ki67 proteins were evaluated by quantitative real-time PCR and immunohistochemistry respectively. Anterior normal pituitaries were used as controls. Associations between molecular findings and clinical data were analyzed.
The aCPs presented higher mRNA expression of SHH (+400-fold change (FC); P<0.01), GLI1 (+102-FC; P<0.001), and GLI3 (+5.1-FC; P<0.01) than normal anterior pituitaries. Longer disease-free survival was associated with low SMO and SUFU mRNA expression (P<0.01 and P=0.02 respectively). CTNNB1/β-catenin mutations were found in 47% of the samples. aCPs with identified mutations presented with higher mRNA expression of SMO and GLI1 (+4.3-FC; P=0.02 and +10.2-FC; P=0.03 respectively). SMO, GLI1, GLI3, and SUFU staining was found in 85, 67, 93, and 64% of the samples respectively. Strong GLI1 and GLI3 staining was detected in palisade cells, which also labeled Ki67, a marker of cell proliferation.
The upregulation of SHH signaling occurs in aCPs. Thus, activation of Wnt/β-catenin and SHH pathways, both of which are important in pituitary embryogenesis, appears to contribute to the pathogenesis of aCP.