Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol).
The prostate is a target organ of vitamin D receptor (VDR) agonists and represents an extra-renal site of 1,25-dihydroxyvitamin D(3) synthesis, but its capacity to respond to VDR agonists has, so far, been almost exclusively probed for the treatment of prostate cancer. We have analyzed the capacity of VDR agonists to treat benign prostatic hyperplasia (BPH), a complex syndrome characterized by a static component related to prostate overgrowth, a dynamic one responsible for urinary irritative symptoms, and an inflammatory component. Preclinical data demonstrate that VDR agonists, and notably BXL-628 (elocalcitol), reduce the static component of BPH by inhibiting the activity of intra-prostatic growth factors downstream of the androgen receptor, and the dynamic component by targeting bladder cells. In addition, BXL-628 inhibits production of proinflammatory cytokines and chemokines by human BPH cells. These data have led to a proof-of-concept clinical study that has successfully shown arrest of prostate growth in BPH patients treated with BXL-628, with excellent safety. We have documented the anti-inflammatory effects of BXL-628 also in animal models of autoimmune prostatitis, observing a significant reduction of intra-prostatic cell infiltrate following administration of this VDR agonist, at normocalcemic doses, in mice with already established disease. These data extend the potential use of VDR agonists to novel indications that represent important unmet medical needs, and provide a sound rationale for further clinical testing.
Adorini
Luciano
L
BioXell, Via Olgettina 58, I-20132 Milan, Italy. Luciano.Adorini@bioxell.com
Penna
Giuseppe
G
Amuchastegui
Susana
S
Cossetti
Chiara
C
Aquilano
Francesca
F
Mariani
Roberto
R
Fibbi
Benedetta
B
Morelli
Annamaria
A
Uskokovic
Milan
M
Colli
Enrico
E
Maggi
Mario
M
D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism
C487049:BXL628; D018167:Receptors, Calcitriol; D002117:Calcitriol