Pre-clinical evidence and clinical translation of benign prostatic hyperplasia treatment by the vitamin D receptor agonist BXL-628 (Elocalcitol).
The active form of vitamin D, 1,25-dihydroxyvitamin D3, is a secosteroid hormone that binds to the vitamin D receptor (VDR), a member of the superfamily of nuclear receptors, and exerts a number of diverse biological functions. The natural hormone and synthetic VDR agonists are well known for their capacity to control calcium and bone metabolism, but they also regulate proliferation and differentiation of many cell types, and possess exquisite immunoregulatory properties, mostly by targeting dendritic cells (DC) and T cells. These properties have been clinically exploited in the treatment of different diseases, from secondary hyperparathyroidism to osteoporosis to psoriasis. The VDR is expressed by most cell types, including cells of the urogenital system such as prostate and bladder cells. In particular, the prostate has been recognized as a target organ of VDR agonists and represents an extra-renal synthesis site of 1,25-dihydroxyvitamin D3, but its capacity to respond to VDR agonists has, so far, been probed only for the treatment of prostate cancer. We have taken a different approach, and have analysed 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 component responsible for urinary irritative symptoms, and a possible inflammatory component. Pre-clinical data reviewed here 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. 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. Ongoing clinical studies will assess the capacity of this VDR agonist to reduce symptoms and ameliorate flow parameters in BPH-affected individuals. The pronounced effects of BXL-628 on bladder smooth muscle cells and its anti-inflammatory properties indeed anticipate beneficial effects also on BPH-related lower urinary tract symptoms.
Maggi
M
M
Department of Clinical Physiopathology, Center of Research, Transfer and High Education (DENOTHE), University of Florence, Florence, Italy.
Crescioli
C
C
Morelli
A
A
Colli
E
E
Adorini
L
L
D000728:Androgens / Q000502:physiology; D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008297:Male; D008954:Models, Biological; D011467:Prostate / Q000187:drug effects / Q000502:physiology; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000209:etiology; D018167:Receptors, Calcitriol / Q000819:agonists / Q000378:metabolism*
D000728:Androgens; C487049:BXL628; D006133:Growth Substances; D018836:Inflammation Mediators; D018167:Receptors, Calcitriol; D002117:Calcitriol