Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia.
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.


METHODS
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.
Crescioli
C
C
Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Ferruzzi
P
P
Caporali
A
A
Scaltriti
M
M
Bettuzzi
S
S
Mancina
R
R
Gelmini
S
S
Serio
M
M
Villari
D
D
Vannelli
G B
GB
Colli
E
E
Adorini
L
L
Maggi
M
M
D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D002455:Cell Division / Q000187:drug effects; D017322:Clinical Trials, Phase II as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D009919:Orchiectomy; D011467:Prostate / Q000187:drug effects* / Q000473:pathology; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology; D016032:Randomized Controlled Trials as Topic; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured / Q000187:drug effects
C487049:BXL628; D002117:Calcitriol