Inhibition of spontaneous and androgen-induced prostate growth by a nonhypercalcemic calcitriol analog.
We have recently found that analog V (BXL-353, a calcitriol analog) inhibits growth factor (GF)-stimulated human benign prostate hyperplasia (BPH) cell proliferation by disrupting signal transduction, reducing Bcl-2 expression, and inducing apoptosis. We now report that BXL-353 blocks in vitro and in vivo testosterone (T) activity. BPH cells responded to T and dihydrotestosterone (DHT) with dose-dependent growth and reduced apoptosis. Exposure of BPH cells to BXL-353 significantly antagonized both T- and DHT-induced proliferation and induced apoptosis, even in the presence of T. To verify whether BXL-353 reduced prostate growth in vivo, we administered it orally to either intact or castrated rats, supplemented with T enanthate. Nonhypercalcemic doses of BXL-353 time- and dose-dependently reduced the androgen effect on ventral prostate weight, similarly to finasteride. Comparable results were obtained after chronic administration of BXL-353 to intact rats. Clusterin (an atrophy marker) gene and protein were up-regulated by BXL-353 in rat prostate, and nuclear fragmentation was widely present. The antiandrogenic properties of BXL-353 did not interfere with pituitary and testis function, as assessed by serum determination of rat LH and T. BXL-353 did not compete for androgen binding to BPH homogenates and failed to inhibit 5alpha-reductase type 1 and type 2 activities. In conclusion, BXL-353 blocks in vitro and in vivo androgen-stimulated prostate cell growth, probably acting downstream from the androgen receptor, without affecting calcemia or sex hormone secretion. BXL-353 and other vitamin D(3) analogs might thus represent an interesting class of compounds for treating patients with BPH.
Crescioli
C
C
Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
Ferruzzi
P
P
Caporali
A
A
Mancina
R
R
Comerci
A
A
Muratori
M
M
Scaltriti
M
M
Vannelli
G B
GB
Smiroldo
S
S
Mariani
R
R
Villari
D
D
Bettuzzi
S
S
Serio
M
M
Adorini
L
L
Maggi
M
M
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000235:genetics; D000375:Aging / Q000473:pathology; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D016466:CHO Cells; D002117:Calcitriol / Q000031:analogs & derivatives*; D051152:Clusterin; D006224:Cricetinae; D013196:Dihydrotestosterone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000473:pathology*; D011470:Prostatic Hyperplasia / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051497:Receptor, Fibroblast Growth Factor, Type 2; D011944:Receptors, Androgen / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects; D013739:Testosterone / Q000097:blood / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D000726:Androgen Antagonists; C495242:CLU protein, human; D051152:Clusterin; D006023:Glycoproteins; D012739:Gonadal Steroid Hormones; D018832:Molecular Chaperones; D011944:Receptors, Androgen; D017468:Receptors, Fibroblast Growth Factor; D013196:Dihydrotestosterone; D013739:Testosterone; D007986:Luteinizing Hormone; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; D002117:Calcitriol