Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol)
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Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693
Inhibition of prostate growth and inflammation by the
vitamin D receptor agonist BXL-628 (elocalcitol)
Luciano Adorini a,∗ , Giuseppe Penna a , Susana Amuchastegui a , Chiara Cossetti a ,
Francesca Aquilano a , Roberto Mariani a , Benedetta Fibbi b , Annamaria Morelli b ,
Milan Uskokovic c , Enrico Colli a , Mario Maggi b
a BioXell, 20132 Milan, Italy
b Andrology Unit, University of Florence, 50139 Florence, Italy
c BioXell Inc., 07110 Nutley, NJ, USA
Received 30 November 2006
Abstract
The prostate is a target organ of vitamin D receptor (VDR) agonists and represents an extra-renal site of 1,25-dihydroxyvitamin D3
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.
© 2006 Elsevier Ltd. All rights reserved.
Keywords: Benign prostatic hyperplasia; Chronic prostatitis/chronic pelvic pain syndrome; Vitamin D analogs
1. Introduction and a multimember coactivator complex, the D receptor
interacting proteins. These coactivators induce chromatin
1,25-Dihydroxyvitamin D3 [1,25(OH)2 D3 ] binds with remodelling through intrinsic histone-modifying activities,
high affinity to the vitamin D receptor (VDR), a ligand- and direct recruitment of key transcription initiation compo-
activated nuclear transcription factor regulating specific nents at regulated promoters. Thus, the VDR functions as
gene expression in target tissues. Agonist binding induces an agonist-activated transcription factor that binds to specific
conformational changes in the VDR, which promote het- DNA sequence elements in vitamin D responsive genes (vita-
erodimerization with the retinoid X receptor (RXR) and min D responsive elements, VDRE) and ultimately influences
recruitment of a number of corepressor and coactivator pro- the rate of RNA polymerase II-mediated gene transcription
teins, including steroid receptor coactivator family members [1].
VDR agonists have different clinical applications, and
∗ Corresponding author at: BioXell, Via Olgettina 58, I-20132 Milan, Italy. they are currently used in the treatment of secondary
Tel.: +39 02 21049570; fax: +39 02 21049555. hyperparathyroidism, osteoporosis, and psoriasis [2]. More
E-mail address: Luciano.Adorini@bioxell.com (L. Adorini). recently, the biological actions of VDR agonists have been
0960-0760/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jsbmb.2006.12.065690 L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693
shown to extend well beyond calcium metabolism to include sion has also been detected in cultured stromal cells derived
regulation of immune responses, angiogenesis, and growth from prostate and bladder of BPH patients [17,18]. Expres-
differentiation and apoptosis of many cell types, including sion of VDR in cultured human epithelial cells from prostate
malignant cells [3]. gland have been also described, at higher levels than in cor-
The discovery of VDR expression in most cell types of the responding stromal cells [19]. In addition, it is well known
immune system prompted a number of studies investigating that malignant prostate cell lines express the VDR [20,21].
the capacity of VDR agonists to modulate immune responses Interestingly, epithelial prostate cells express the enzyme 1␣-
[4]. VDR agonists were found to be selective inhibitors of hydroxylase, required for 1,25(OH)2 D3 synthesis [22], and
Th1 cell development [5,6], and to inhibit directly Th1-type the extra-renal synthesis of 1,25(OH)2 D3 in the prostate could
cytokines such as IL-2 and IFN-␥ [7,8]. 1,25(OH)2 D3 has have a growth-regulating role, as suggested by the marked
also been shown, in some cases, to enhance the develop- decrease of 1␣-hydroxylase activity in prostate cancer cell
ment of Th2 cells via a direct effect on naı̈ve CD4+ cells lines [23].
[9]. In addition to exerting direct effects on T cell activation,
VDR agonists markedly modulate the phenotype and func-
tion of antigen-presenting cells (APCs), and in particular of 3. Inhibition of prostate cell growth by VDR
dendritic cells (DCs), leading them to acquire tolerogenic agonists: in vitro and in vivo evidence from
properties that favor the induction of regulatory rather than experimental models
effector T cells [10]. Thus, DCs appear to be primary targets
for the tolerogenic properties of VDR agonists, and sev- Because human and rat prostate cells express VDR and
eral immunomodulatory effects could be mediated by their respond to VDR agonists by decreasing their proliferation,
capacity to inhibit the nuclear factor NF-B in DCs [11], a we originally hypothesized [24] that VDR agonists could rep-
transcription factor critical for the production of proinflam- resent a novel option for the treatment of BPH. However, a
matory cytokines and chemokines. In addition, inhibition of problem with the therapeutic use of VDR agonists is their
leukocyte infiltration into inflammatory sites by treatment propensity to induce hypercalcemia and hyperphosphatemia.
with VDR agonists is associated with their capacity to inhibit VDR agonists retaining biological activity but devoid of
chemokine production by cells in the target organ via inhibi- hypercalcemic side effects have been developed, and some of
tion of NF-B activation. This has been convincingly shown them approved for the treatment of secondary hyperparathy-
in nonobese diabetic (NOD) mice by arrest of insulitis, with roidism and osteoporosis [25]. Hence, non-hypercalcemic
block of Th1 cell infiltration into the pancreas, and inhibi- 1,25-dihydroxyvitamin D3 analogues could represent good
tion of type 1 diabetes development associated with reduced candidates to become novel and attractive therapeutic agents
chemokine production by islet cells [12]. for BPH.
Based on this and additional evidence, VDR agonists are Right from the earliest experiments, we have consistently
currently considered as potential drugs for the treatment of observed that VDR agonists have the ability to decrease stro-
systemic autoimmune diseases [13] and allograft rejection mal prostate cell proliferation and induce apoptosis [24]. In
[14,15]. In addition, sound epidemiological data supporting particular, BXL-628 (elocalcitol, 1-␣-fluoro-25-hydroxy-
the association between vitamin D and cancer, coupled with 16,23E-diene-26,27-bishomo-20-epi-cholecalciferol, see
the capacity of VDR agonists to inhibit cell growth, pro- Fig. 1) decreased testosterone (T)-stimulated human BPH
mote apoptosis, and favor cell differentiation have provided cell proliferation similarly to finasteride and cyproterone
the basis for extensive efforts aiming at the development of acetate, and promoted BPH cell apoptosis even in the
these hormones as anti-cancer agents [16]. Since, as dis- presence of growth factors [26]. However, this analogue
cussed below, the prostate is a target organ of VDR agonists, does not directly interfere with androgen receptor (AR)
their cell growth inhibitory properties and immunomodula- signalling because it does not affect 5(-reductase type
tory activities may also find applications not only in prostate 1 and 2 activity, it fails to bind to the AR, and it does
cancer, but also in the treatment of different prostate diseases not affect AR transcriptional activity [26]. Molecular
unrelated to cancer, from benign prostatic hyperplasia (BPH)
to non-bacterial chronic prostatitis.
2. VDR expression in prostate cells
The VDR is not only present in classic target tissues as
bone, bowel and kidney, but is also expressed in several other
human tissues, including those derived from the urogeni-
tal sinus, as prostate and bladder [17]. In particular, VDR
expression in these tissues is quantitatively similar to classic Fig. 1. Structure of BXL-628 and the native hormone 1,25-dihydroxy-
target organs such as liver, kidney, and bone. VDR expres- vitamin D3.L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693 691
Fig. 2. Inhibition of prostate weight in beagle dogs treated with BXL-628. Adult beagle male dogs were treated daily orally for 9 months with vehicle alone
or containing 5 g/kg BXL-628. At the end of the dosing period, and after a 2-month recovery, the prostate weight was determined, and is shown as ratio to
body weight. Serum calcium levels were also determined at the end of the dosing period, and after a 2-month recovery. BXL-628 decreases prostate weight in
beagle dogs, an animal species that naturally develops BPH, without increasing serum calcium levels.
mechanisms involved in mediating the anti-proliferative 4. Arrest of prostate growth in BPH patients by
and pro-apoptotic effects of BXL-628 were therefore BXL-628 treatment
hypothesized to operate downstream the AR. We have par-
tially characterized these molecular events, which include The preclinical results reviewed above prompted a clinical
decreased auto-phosphorylation of growth factor receptors investigation of BXL-628 in BPH patients. A multi-centre,
specific for KGF and IGF-1, arrest of cell cycle progression double blind, randomized, placebo controlled, parallel group,
at G1, and decreased expression of the survival factor bcl-2 phase IIa clinical study was therefore conducted to assess
[26]. the efficacy and safety of BXL-628 in patients with BPH
To test whether or not BXL-628 could decrease spon- [27]. Eligible patients (aged ≥50 years, prostate volume
taneous or androgen-mediated prostate growth in vivo, we ≥40 ml) were randomly assigned to BXL-628 150 g daily
studied the rat ventral prostate, the most T-sensitive prostate or placebo for 12 weeks. At baseline and at the end of
area in rodents [26]. We found that BXL-628 treatment can the study all randomized patients underwent pelvic MRI to
significantly reduce prostate growth in both naı̈ve adult rats, measure prostate volume, as well as testing for uroflowme-
and in castrated, T-replaced rats, with an effect comparable to try, serum PSA, testosterone, dihydrotestosterone and LH
finasteride. Interestingly, at prostate growth inhibitory con- serum levels. A total of 119 patients were randomized: 57
centrations, BXL-628 did not affect pituitary or testicular patients to BXL-628 and 62 to placebo. The percentage
hormone secretion and did not increase calcemia [26]. As change of prostate volume at 12 weeks was −2.9 ± 0.8 in
predicted from in vitro studies, apoptosis was evident in both the BXL-628 group versus +4.3 ± 0.8 in the placebo group
epithelial and stromal prostate cells from BXL-628-treated (P < 0.0001). The estimated difference between treatments
rats, associated with increased expression of clusterin [26], a (BXL-628 minus placebo) was −7.22 (95% confidence limits
marker of cell death and inhibition of cell cycle progression. between −9.27 and −5.18). These results confirm the hypoth-
To further verify the inhibitory effect on prostate growth of esis, predicted by our preclinical studies, that BXL-628 is
BXL-628 in other animal species, we chronically treated male able to arrest prostate growth in BPH patients. Interestingly,
beagle dogs. After a 9-month administration of BXL-628 neither serum nor urinary calcium levels changed signifi-
(5 g/kg/day per os), the prostate weight of treated dogs was cantly in BXL-628 treated patients during the course of the
substantially lower that in vehicle-treated controls, although study. Sexual side effects, often present in patients treated
the limited number of dogs/group did not allow reaching sta- with 5␣-reductase inhibitors, were nearly absent in the BXL-
tistical significance (Fig. 2). Reduction of prostate weight 628 arm, and even lower than in the placebo arm [27]. In
was even more evident after a 2-month recovery (Fig. 2), this study, PSA increase was lower in the active-treated than
suggesting a sustained effect of BXL-628 treatment. This in the placebo group, although this difference resulted not
experiment demonstrates the ability of BXL-628 to decrease significant. Hence, results from the already ongoing double-
prostate growth also in animal species that spontaneously blind, randomized, placebo controlled, 6-month long, phase
develop BPH. Interestingly, even after prolonged BXL-628 IIb trial on over 500 BPH patients are eagerly awaited.
administration, no increase in serum calcium levels was noted In the 12-week phase IIa trial, no difference was observed
(Fig. 2). in symptom score or uroflowmetry parameters [27]. The lack692 L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693
of variation in these clinical parameters – in spite of a highly pathogenic events in already established EAP in the NOD
significant reduction of prostate growth – might be justified mouse. These data support the autoimmune pathogenesis of
by the short duration of this proof-of-concept study, and by CP/CPPS, and indicate that treatment with the VDR agonist
the fact that patients were not screened for symptoms but only BXL-628 may prove clinically beneficial in this syndrome. To
for prostatic volume. To clarify this point, a 6-month-long establish a clinical proof of concept, a randomized, double-
phase IIb study, measuring maximum urinary flow rate and blind, placebo controlled, parallel group study to determine
symptom severity as secondary end-points in patients with at the effect of BXL-628 in CP/CPPS patients is ongoing. Anal-
least moderate symptomatology, is currently in progress. ysis of several proinflammatory cytokines and chemokines in
seminal fluids indicate IL-8 concentration, a secondary end-
point in the trial, as a reliable surrogate marker for treatment
5. Inhibition of prostate inflammation by BXL-628 efficacy.
Thus, the anti-inflammatory and immunomodulatory
An inflammatory component, revealed by prostatic properties of BXL-628, demonstrated in vitro in BPH cell
inflammatory infiltrates, is observed in a large percentage cultures and in vivo in an experimental model of autoim-
of BPH surgical specimens from patients without prostati- mune prostatitis, could turn out to be beneficial both in BPH
tis symptoms [28,29]. These inflammatory cells might be and in CP/CPPS patients.
responsible for several biological changes leading to prostate
overgrowth and for prostatitis-like symptoms associated with
BPH in at least 20% of patients [30]. In addition, accumulat- 6. Conclusions
ing evidence indicates a role for cytokines and chemokines,
whose levels are increased not only in patients with chronic The preclinical and clinical data reviewed here show that
prostatitis/chronic pelvic pain syndrome (CP/CPPS) but also BXL-628 is able to inhibit prostate growth, and indicate its
in BPH patients [31]. Up-regulation of proinflammatory ability to control prostate inflammation. Different mecha-
cytokines has been described in BPH patients and associ- nisms of action account for the capacity of BXL-628 to reduce
ated to oxidative stress and stromal tissue-remodeling [32]. the static component of BPH, from induction of apoptosis
Interestingly, IL-1␣ and IL-8 are known to induce KGF and in prostate cells to inhibition of intra-prostatic growth fac-
FGF-2 expression in cultured BPH cells [33,34], and IL-8 can tor activity downstream the AR. In addition, BXL-628 could
directly promote proliferation of BPH cells [35]. A chronic affect the dynamic component of BPH by targeting blad-
inflammatory response might thus trigger transdifferentia- der cells [17], and have beneficial effects also by controlling
tion of resident stromal cells, resulting in a sustained prostate the inflammatory response in the prostate of BPH patients.
overgrowth through its growth factors, a situation similar to Ongoing clinical studies will show whether or not this drug
wound healing [36]. is also able to reduce symptoms and ameliorate flow param-
CP/CPPS (chronic non-bacterial prostatitis, NIH category eters in BPH-affected individuals. The pronounced effects
III) is a highly prevalent syndrome of suspected autoim- of BXL-628 on bladder smooth muscle cells and its anti-
mune origin [37]. Based on the marked inhibitory activity inflammatory properties are promising features for beneficial
of the VDR agonist BXL-628 on basal and growth factor- effects also on lower urinary tract symptoms. In addition, the
induced proliferation of human prostate cells, and on its anti-inflammatory properties of BXL-628, demonstrated in
potent anti-inflammatory properties in different models, we an experimental model of autoimmune prostatitis, could be
have tested its capacity to treat experimental autoimmune translated to the treatment of CP/CPPS. Indeed, as CP/CPPS
prostatitis (EAP). EAP was induced in non obese diabetic and BPH are two conditions characterized by both prostate
(NOD) mice, a strain genetically prone to develop differ- inflammation and cell proliferation, treatment with BXL-628
ent autoimmune diseases, by injection of mouse prostate may prove efficacious in both indications.
homogenate in CFA [38]. BXL-628 was administered orally
5 dose/week at 100 g/kg from day 14 to 28 post immu-
nization. Administration of BXL-628, at non hypercalcemic Acknowledgment
doses, for 2 weeks in already established EAP inhibits signif-
icantly the intra-prostatic cell infiltrate, leading to a profound Supported in part by the European Community grant
reduction in the number of CD4+ and CD8+ T cells, B INNOCHEM to L.A.
cells, macrophages and dendritic cells. Immunohistologi-
cal analysis demonstrates decreased cell proliferation and
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