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Inhibition of Spontaneous and Androgen-Induced Prostate Growth by a Nonhypercalcemic Calcitriol Analog

Departments of Clinical Physiopathology (C.C., P.F., R.M., A.C., M.M., M.S., M.M.), Anatomy, Histology, and Forensic Medicine (G.B.V.), and Urology (D.V.), University of Florence, Florence 50100, Italy; Department of Experimental Medicine, University of Parma (A.C., S.B.), Parma 43100, Italy; BioXell (S.S., R.M., L.A.), Milan 20132, Italy; and Department of Biomedical Science, University of Modena and Reggio Emilia (M.S.), Modena 41100, Italy

Address all correspondence and requests for reprints to: Prof. Mario Maggi, Dipartimento di Fisiopatologia Clinica, Unità di Andrologia, Università di Firenze, Viale Pieraccini 6, 50139 Florence, Italy. E-mail: m.maggi{at}dfc.unifi.it.

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 5-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 D₃ analogs might thus represent an interesting class of compounds for treating patients with BPH.

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