Inhibition of Prostate Growth and Inflammation by the Vitamin D Receptor Agonist BXL-628 Elocalcitol

8/7/2019 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) 689693

Inhibition of prostate growth and inflammation by thevitamin 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, Italyb 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 D 3synthesis, 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 dataextend 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)2D3] binds with

high affinity to the vitamin D receptor (VDR), a ligand-

activated nuclear transcription factor regulating specificgene expression in target tissues. Agonist binding induces

conformational changes in the VDR, which promote het-

erodimerization with the retinoid X receptor (RXR) and

recruitment of a number of corepressor and coactivator pro-

teins, including steroid receptor coactivator family members

Correspondingauthorat: BioXell,Via Olgettina58, I-20132Milan,Italy.

Tel.: +39 02 21049570; fax: +39 02 21049555.

E-mail address: [email protected](L. Adorini).

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 compo-

nents at regulated promoters. Thus, the VDR functions asan agonist-activated transcription factor that binds to specific

DNA sequence elements in vitamin D responsive genes (vita-

min D responsive elements, VDRE) and ultimatelyinfluences

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

0960-0760/$ see front matter 2006 Elsevier Ltd. All rights reserved.

doi:10.1016/j.jsbmb.2006.12.065
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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)2D3 has

also been shown, in some cases, to enhance the develop-

ment of Th2 cells via a direct effect on nave CD4+ cells

[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

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 sev-

eral immunomodulatory effects could be mediated by theircapacity to inhibit the nuclear factor NF-B in DCs [11], a

transcription factor critical for the production of proinflam-

matory 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 inhibi-

tion 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 inhibi-

tion of type 1 diabetes development associated with reduced

chemokine production by islet cells [12].

Based on this and additional evidence, VDR agonists arecurrently 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, pro-

mote 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 dis-

cussed below, the prostate is a target organ of VDR agonists,

their cell growth inhibitory properties and immunomodula-

tory 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.

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

target organs such as liver, kidney, and bone. VDR expres-

sion has also been detected in cultured stromal cells derived

from prostate and bladder of BPH patients [17,18]. Expres-

sion of VDR in cultured human epithelial cells from prostate

gland have been also described, at higher levels than in cor-

responding 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)2D3 synthesis [22], and

the extra-renal synthesisof 1,25(OH)2D3 in theprostatecould

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] thatVDR agonists could rep-

resent 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 hyperparathy-

roidism 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 consistentlyobserved that VDR agonists have the ability to decrease stro-

mal prostate cell proliferation and induce apoptosis [24]. In

particular, BXL-628 (elocalcitol, 1--fluoro-25-hydroxy-

16,23E-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

Fig. 1. Structure of BXL-628 and the native hormone 1,25-dihydroxy-

vitamin D3.


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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 5g/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 par-

tially 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 spon-

taneous or androgen-mediated prostate growth in vivo, we

studied the rat ventral prostate, the most T-sensitive prostatearea in rodents [26]. We found that BXL-628 treatment can

significantly reduce prostate growth in both nave adult rats,

and in castrated, T-replaced rats, with an effect comparable to

finasteride. Interestingly, at prostate growth inhibitory con-

centrations, 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 growthof

BXL-628 in otheranimal species,we chronically treated male

beagle dogs. After a 9-month administration of BXL-628(5g/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 sta-

tistical 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 150g daily

or placebo for 12 weeks. At baseline and at the end ofthe study all randomized patients underwent pelvic MRI to

measure prostate volume, as well as testing for uroflowme-

try, 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 minusplacebo) was7.22 (95% confidence limits

between9.27and5.18). These results confirm the hypoth-

esis, 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 signifi-cantly 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 BXL-

628 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 double-

blind, 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 atleast 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 prostati-

tis 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, accumulat-

ing 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 associ-

ated 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 BPHcells [33,34], andIL-8 can

directly promote proliferation of BPH cells [35]. A chronic

inflammatory response might thus trigger transdifferentia-

tion 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 autoim-

mune origin [37]. Based on the marked inhibitory activity

of the VDR agonist BXL-628 on basal and growth factor-

induced 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 differ-

ent autoimmune diseases, by injection of mouse prostate

homogenate in CFA [38]. BXL-628 was administered orally

5 dose/week at 100g/kg from day 14 to 28 post immu-

nization. Administration of BXL-628, at non hypercalcemic

doses, for 2 weeks in already established EAP inhibits signif-

icantly 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. Immunohistologi-

cal 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 clinicallybeneficialin this syndrome.To

establish a clinical proof of concept, a randomized, double-

blind, placebo controlled, parallel group study to determine

the effect of BXL-628 in CP/CPPS patients is ongoing. Anal-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

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 autoim-

mune 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 mecha-

nismsofactionaccountforthecapacityofBXL-628toreduce

the static component of BPH, from induction of apoptosis

in prostate cells to inhibition of intra-prostatic growth fac-

tor activity downstream the AR. In addition, BXL-628 could

affect the dynamic component of BPH by targeting blad-

der 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 param-eters in BPH-affected individuals. The pronounced effects

of BXL-628 on bladder smooth muscle cells and its anti-

inflammatory 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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Inhibition of Prostate Growth and Inflammation by the Vitamin D Receptor Agonist BXL-628 Elocalcitol

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