Inhibition of prostate growth and inflammation by the

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
b
a BioXell, 20132 Milan, Italy
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 intraprostatic 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
1,25-Dihydroxyvitamin D3 [1,25(OH)2 D3 ] binds with
high affinity to the vitamin D receptor (VDR), a ligandactivated nuclear transcription factor regulating specific
gene expression in target tissues. Agonist binding induces
conformational changes in the VDR, which promote heterodimerization with the retinoid X receptor (RXR) and
recruitment of a number of corepressor and coactivator proteins, including steroid receptor coactivator family members
∗ Corresponding author at: BioXell, Via Olgettina 58, I-20132 Milan, Italy.
Tel.: +39 02 21049570; fax: +39 02 21049555.
E-mail address: Luciano.Adorini@bioxell.com (L. Adorini).
0960-0760/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.jsbmb.2006.12.065
and a multimember coactivator complex, the D receptor
interacting proteins. These coactivators induce chromatin
remodelling through intrinsic histone-modifying activities,
and direct recruitment of key transcription initiation components at regulated promoters. Thus, the VDR functions as
an agonist-activated transcription factor that binds to specific
DNA sequence elements in vitamin D responsive genes (vitamin D responsive elements, VDRE) and ultimately influences
the rate of RNA polymerase II-mediated gene transcription
[1].
VDR agonists have different clinical applications, and
they are currently used in the treatment of secondary
hyperparathyroidism, osteoporosis, and psoriasis [2]. More
recently, the biological actions of VDR agonists have been
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L. Adorini et al. / Journal of Steroid Biochemistry & Molecular Biology 103 (2007) 689–693
shown to extend well beyond calcium metabolism to include
regulation of immune responses, angiogenesis, and growth
differentiation and apoptosis of many cell types, including
malignant cells [3].
The discovery of VDR expression in most cell types of the
immune system prompted a number of studies investigating
the capacity of VDR agonists to modulate immune responses
[4]. VDR agonists were found to be selective inhibitors of
Th1 cell development [5,6], and to inhibit directly Th1-type
cytokines such as IL-2 and IFN-␥ [7,8]. 1,25(OH)2 D3 has
also been shown, in some cases, to enhance the development of Th2 cells via a direct effect on naı̈ve CD4+ cells
[9]. In addition to exerting direct effects on T cell activation,
VDR agonists markedly modulate the phenotype and function of antigen-presenting cells (APCs), and in particular of
dendritic cells (DCs), leading them to acquire tolerogenic
properties that favor the induction of regulatory rather than
effector T cells [10]. Thus, DCs appear to be primary targets
for the tolerogenic properties of VDR agonists, and several immunomodulatory effects could be mediated by their
capacity to inhibit the nuclear factor NF-␬B in DCs [11], a
transcription factor critical for the production of proinflammatory cytokines and chemokines. In addition, inhibition of
leukocyte infiltration into inflammatory sites by treatment
with VDR agonists is associated with their capacity to inhibit
chemokine production by cells in the target organ via inhibition of NF-␬B activation. This has been convincingly shown
in nonobese diabetic (NOD) mice by arrest of insulitis, with
block of Th1 cell infiltration into the pancreas, and inhibition of type 1 diabetes development associated with reduced
chemokine production by islet cells [12].
Based on this and additional evidence, VDR agonists are
currently considered as potential drugs for the treatment of
systemic autoimmune diseases [13] and allograft rejection
[14,15]. In addition, sound epidemiological data supporting
the association between vitamin D and cancer, coupled with
the capacity of VDR agonists to inhibit cell growth, promote apoptosis, and favor cell differentiation have provided
the basis for extensive efforts aiming at the development of
these hormones as anti-cancer agents [16]. Since, as discussed below, the prostate is a target organ of VDR agonists,
their cell growth inhibitory properties and immunomodulatory activities may also find applications not only in prostate
cancer, but also in the treatment of different prostate diseases
unrelated to cancer, from benign prostatic hyperplasia (BPH)
to non-bacterial chronic prostatitis.
sion has also been detected in cultured stromal cells derived
from prostate and bladder of BPH patients [17,18]. Expression of VDR in cultured human epithelial cells from prostate
gland have been also described, at higher levels than in corresponding stromal cells [19]. In addition, it is well known
that malignant prostate cell lines express the VDR [20,21].
Interestingly, epithelial prostate cells express the enzyme 1␣hydroxylase, required for 1,25(OH)2 D3 synthesis [22], and
the extra-renal synthesis of 1,25(OH)2 D3 in the prostate could
have a growth-regulating role, as suggested by the marked
decrease of 1␣-hydroxylase activity in prostate cancer cell
lines [23].
3. Inhibition of prostate cell growth by VDR
agonists: in vitro and in vivo evidence from
experimental models
Because human and rat prostate cells express VDR and
respond to VDR agonists by decreasing their proliferation,
we originally hypothesized [24] that VDR agonists could represent a novel option for the treatment of BPH. However, a
problem with the therapeutic use of VDR agonists is their
propensity to induce hypercalcemia and hyperphosphatemia.
VDR agonists retaining biological activity but devoid of
hypercalcemic side effects have been developed, and some of
them approved for the treatment of secondary hyperparathyroidism and osteoporosis [25]. Hence, non-hypercalcemic
1,25-dihydroxyvitamin D3 analogues could represent good
candidates to become novel and attractive therapeutic agents
for BPH.
Right from the earliest experiments, we have consistently
observed that VDR agonists have the ability to decrease stromal prostate cell proliferation and induce apoptosis [24]. In
particular, BXL-628 (elocalcitol, 1-␣-fluoro-25-hydroxy16,23E-diene-26,27-bishomo-20-epi-cholecalciferol,
see
Fig. 1) decreased testosterone (T)-stimulated human BPH
cell proliferation similarly to finasteride and cyproterone
acetate, and promoted BPH cell apoptosis even in the
presence of growth factors [26]. However, this analogue
does not directly interfere with androgen receptor (AR)
signalling because it does not affect 5(-reductase type
1 and 2 activity, it fails to bind to the AR, and it does
not affect AR transcriptional activity [26]. Molecular
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 urogenital sinus, as prostate and bladder [17]. In particular, VDR
expression in these tissues is quantitatively similar to classic
target organs such as liver, kidney, and bone. VDR expres-
Fig. 1. Structure of BXL-628 and the native hormone 1,25-dihydroxyvitamin 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
and pro-apoptotic effects of BXL-628 were therefore
hypothesized to operate downstream the AR. We have partially characterized these molecular events, which include
decreased auto-phosphorylation of growth factor receptors
specific for KGF and IGF-1, arrest of cell cycle progression
at G1, and decreased expression of the survival factor bcl-2
[26].
To test whether or not BXL-628 could decrease spontaneous or androgen-mediated prostate growth in vivo, we
studied the rat ventral prostate, the most T-sensitive prostate
area in rodents [26]. We found that BXL-628 treatment can
significantly reduce prostate growth in both naı̈ve adult rats,
and in castrated, T-replaced rats, with an effect comparable to
finasteride. Interestingly, at prostate growth inhibitory concentrations, BXL-628 did not affect pituitary or testicular
hormone secretion and did not increase calcemia [26]. As
predicted from in vitro studies, apoptosis was evident in both
epithelial and stromal prostate cells from BXL-628-treated
rats, associated with increased expression of clusterin [26], a
marker of cell death and inhibition of cell cycle progression.
To further verify the inhibitory effect on prostate growth of
BXL-628 in other animal species, we chronically treated male
beagle dogs. After a 9-month administration of BXL-628
(5 ␮g/kg/day per os), the prostate weight of treated dogs was
substantially lower that in vehicle-treated controls, although
the limited number of dogs/group did not allow reaching statistical significance (Fig. 2). Reduction of prostate weight
was even more evident after a 2-month recovery (Fig. 2),
suggesting a sustained effect of BXL-628 treatment. This
experiment demonstrates the ability of BXL-628 to decrease
prostate growth also in animal species that spontaneously
develop BPH. Interestingly, even after prolonged BXL-628
administration, no increase in serum calcium levels was noted
(Fig. 2).
4. Arrest of prostate growth in BPH patients by
BXL-628 treatment
The preclinical results reviewed above prompted a clinical
investigation of BXL-628 in BPH patients. A multi-centre,
double blind, randomized, placebo controlled, parallel group,
phase IIa clinical study was therefore conducted to assess
the efficacy and safety of BXL-628 in patients with BPH
[27]. Eligible patients (aged ≥50 years, prostate volume
≥40 ml) were randomly assigned to BXL-628 150 ␮g daily
or placebo for 12 weeks. At baseline and at the end of
the study all randomized patients underwent pelvic MRI to
measure prostate volume, as well as testing for uroflowmetry, serum PSA, testosterone, dihydrotestosterone and LH
serum levels. A total of 119 patients were randomized: 57
patients to BXL-628 and 62 to placebo. The percentage
change of prostate volume at 12 weeks was −2.9 ± 0.8 in
the BXL-628 group versus +4.3 ± 0.8 in the placebo group
(P < 0.0001). The estimated difference between treatments
(BXL-628 minus placebo) was −7.22 (95% confidence limits
between −9.27 and −5.18). These results confirm the hypothesis, predicted by our preclinical studies, that BXL-628 is
able to arrest prostate growth in BPH patients. Interestingly,
neither serum nor urinary calcium levels changed significantly in BXL-628 treated patients during the course of the
study. Sexual side effects, often present in patients treated
with 5␣-reductase inhibitors, were nearly absent in the BXL628 arm, and even lower than in the placebo arm [27]. In
this study, PSA increase was lower in the active-treated than
in the placebo group, although this difference resulted not
significant. Hence, results from the already ongoing doubleblind, randomized, placebo controlled, 6-month long, phase
IIb trial on over 500 BPH patients are eagerly awaited.
In the 12-week phase IIa trial, no difference was observed
in symptom score or uroflowmetry parameters [27]. The lack
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of variation in these clinical parameters – in spite of a highly
significant reduction of prostate growth – might be justified
by the short duration of this proof-of-concept study, and by
the fact that patients were not screened for symptoms but only
for prostatic volume. To clarify this point, a 6-month-long
phase IIb study, measuring maximum urinary flow rate and
symptom severity as secondary end-points in patients with at
least moderate symptomatology, is currently in progress.
5. Inhibition of prostate inflammation by BXL-628
An inflammatory component, revealed by prostatic
inflammatory infiltrates, is observed in a large percentage
of BPH surgical specimens from patients without prostatitis symptoms [28,29]. These inflammatory cells might be
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, accumulating evidence indicates a role for cytokines and chemokines,
whose levels are increased not only in patients with chronic
prostatitis/chronic pelvic pain syndrome (CP/CPPS) but also
in BPH patients [31]. Up-regulation of proinflammatory
cytokines has been described in BPH patients and associated to oxidative stress and stromal tissue-remodeling [32].
Interestingly, IL-1␣ and IL-8 are known to induce KGF and
FGF-2 expression in cultured BPH cells [33,34], and IL-8 can
directly promote proliferation of BPH cells [35]. A chronic
inflammatory response might thus trigger transdifferentiation of resident stromal cells, resulting in a sustained prostate
overgrowth through its growth factors, a situation similar to
wound healing [36].
CP/CPPS (chronic non-bacterial prostatitis, NIH category
III) is a highly prevalent syndrome of suspected autoimmune origin [37]. Based on the marked inhibitory activity
of the VDR agonist BXL-628 on basal and growth factorinduced proliferation of human prostate cells, and on its
potent anti-inflammatory properties in different models, we
have tested its capacity to treat experimental autoimmune
prostatitis (EAP). EAP was induced in non obese diabetic
(NOD) mice, a strain genetically prone to develop different autoimmune diseases, by injection of mouse prostate
homogenate in CFA [38]. BXL-628 was administered orally
5 dose/week at 100 ␮g/kg from day 14 to 28 post immunization. Administration of BXL-628, at non hypercalcemic
doses, for 2 weeks in already established EAP inhibits significantly the intra-prostatic cell infiltrate, leading to a profound
reduction in the number of CD4+ and CD8+ T cells, B
cells, macrophages and dendritic cells. Immunohistological analysis demonstrates decreased cell proliferation and
increased apoptosis. In addition, decreased production of the
proinflammatory cytokines IFN-␥ and IL-17 is observed in
prostate-draining lymph node T cells from BXL-628-treated
NOD mice stimulated by TCR ligation or prostate antigens
(Penna et al., manuscript in preparation). Thus, BXL-628,
at non hypercalcemic doses, is able to interfere with key
pathogenic events in already established EAP in the NOD
mouse. These data support the autoimmune pathogenesis of
CP/CPPS, and indicate that treatment with the VDR agonist
BXL-628 may prove clinically beneficial in this syndrome. To
establish a clinical proof of concept, a randomized, doubleblind, placebo controlled, parallel group study to determine
the effect of BXL-628 in CP/CPPS patients is ongoing. Analysis of several proinflammatory cytokines and chemokines in
seminal fluids indicate IL-8 concentration, a secondary endpoint in the trial, as a reliable surrogate marker for treatment
efficacy.
Thus, the anti-inflammatory and immunomodulatory
properties of BXL-628, demonstrated in vitro in BPH cell
cultures and in vivo in an experimental model of autoimmune prostatitis, could turn out to be beneficial both in BPH
and in CP/CPPS patients.
6. Conclusions
The preclinical and clinical data reviewed here show that
BXL-628 is able to inhibit prostate growth, and indicate its
ability to control prostate inflammation. Different mechanisms of action account for the capacity of BXL-628 to reduce
the static component of BPH, from induction of apoptosis
in prostate cells to inhibition of intra-prostatic growth factor activity downstream the AR. In addition, BXL-628 could
affect the dynamic component of BPH by targeting bladder cells [17], and have beneficial effects also by controlling
the inflammatory response in the prostate of BPH patients.
Ongoing clinical studies will show whether or not this drug
is also able to reduce symptoms and ameliorate flow parameters in BPH-affected individuals. The pronounced effects
of BXL-628 on bladder smooth muscle cells and its antiinflammatory properties are promising features for beneficial
effects also on lower urinary tract symptoms. In addition, the
anti-inflammatory properties of BXL-628, demonstrated in
an experimental model of autoimmune prostatitis, could be
translated to the treatment of CP/CPPS. Indeed, as CP/CPPS
and BPH are two conditions characterized by both prostate
inflammation and cell proliferation, treatment with BXL-628
may prove efficacious in both indications.
Acknowledgment
Supported in part by the European Community grant
INNOCHEM to L.A.
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