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Tumor Biology |
1-Adrenoceptor Antagonists Doxazosin and Terazosin via Induction of Apoptosis1
Division of Urology, Department of Biochemistry and Molecular Biology, and University of Maryland Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 21201
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis
in prostate epithelial and smooth muscle cells in patients with benign
prostatic hypertrophy (BPH; J. Urol., 159:
1810–1815, 1998; J. Urol., 161: 2002–2007, 1999).
In this study, we investigated the biological action of three
1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin,
against prostate cancer cell growth. The antigrowth effect of the three
1-adrenoceptor antagonists was examined in two human prostate cancer
cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary
culture, SMC-1, on the basis of: (a) cell viability
assay; (b) rate of DNA synthesis; and (c)
induction of apoptosis. Our results indicate that treatment of prostate
cancer cells with doxazosin or terazosin results in a significant loss
of cell viability, via induction of apoptosis in a dose-dependent
manner, whereas tamsulosin had no effect on prostate cell growth.
Neither doxazosin nor terazosin exerted a significant effect on the
rate of cell proliferation in prostate cancer cells. Exposure to
phenoxybenzamine, an irreversible inhibitor of 1-adrenoceptors, does
not abrogate the apoptotic effect of doxazosin or terazosin against
human prostate cancer or smooth muscle cells. This suggests that the
apoptotic activity of doxazosin and terazosin against prostate cells is
independent of their capacity to antagonize 1-adrenoceptors.
Furthermore, an in vivo efficacy trial demonstrated that
doxazosin administration (at tolerated pharmacologically relevant
doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in
a significant inhibition of tumor growth. These findings demonstrate
the ability of doxazosin and terazosin (but not tamsulosin) to suppress
prostate cancer cell growth in vitro and in
vivo by inducing apoptosis without affecting cell
proliferation. This evidence provides the rationale for targeting both
drugs, already in clinical use and with established adverse-effect
profiles, against prostatic tumors for the treatment of advanced
prostate cancer. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1-Adrenoceptors are members of the superfamily of G protein-coupled
adrenergic receptors, which mediate actions of the endogenous
catecholamines (norepinephrine and epinephrine), in a variety of target
cells (5)
. Adrenoceptors coupled through G proteins
modulate diverse intracellular processes, including activation of
vascular smooth muscle contraction (6)
, promoting
proliferative responses, such as DNA synthesis, probably through
activation of mitogen-activating protein kinases in vascular smooth
muscle cells (7)
and modulation of cytoskeletal proteins
in prostate smooth muscle cells (8)
. Currently, four
native 1-adrenoceptor subtypes have been identified, 1a, 1b,
1d, and 1L. 1a-Adrenoceptors predominate in the prostate and
bladder trigone (9
, 10)
and are believed to be
functionally important in mediating prostate smooth muscle contraction
(6
, 10) .
The therapeutic benefit of 1-adrenoceptor antagonists in the medical
treatment of
BPH3
is believed to be attributable to a direct action on 1-adrenoceptors
present in prostatic smooth muscle (11
, 12)
. The
documented durability of clinical response to 1 blockade in the face
of ongoing hyperplasia (13)
, however, implies the
existence of several loci on which 1-antagonists could act. Recent
studies from this laboratory have demonstrated that 1-adrenoceptor
antagonists may affect prostate pathophysiology by inducing apoptosis
via mechanisms that transcend smooth muscle relaxation. Treatment of
patients with BPH, with either of the two 1-adrenoceptor antagonists
doxazosin and terazosin, resulted in a significant induction of
apoptosis among the epithelial and smooth muscle cells in the prostate
gland without affecting their proliferative capacity (14
, 15)
. This marked induction of prostate apoptosis correlated with
BPH symptom improvement in response to 1 blockade (14)
.
Our clinical findings are in full accord with experimental studies
using a mouse model of prostate hyperplasia, in which doxazosin
demonstrated a potent apoptotic effect against oncogene-induced
prostate growth, without affecting cellular proliferation
(16)
.
It is our hypothesis in this study that 1-adrenoceptor antagonists
suppress prostate cancer cell growth via induction of apoptosis. To
test this hypothesis, we investigated the antitumor action of three
clinically used 1-adrenoceptor antagonists, doxazosin, terazosin,
and tamsulosin, against human prostate tumor epithelial and smooth
muscle cells. Our findings document the ability of doxazosin and
terazosin, but not tamsulosin, to induce apoptosis in human prostate
cancer cells (within the clinically relevant therapeutic dose range),
potentially via 1-adrenoceptor-independent actions. These results
may have significant therapeutic implications in identifying both
doxazosin and terazosin as potential antitumor agents in the treatment
of advanced prostate cancer.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Drugs.
The three clinically used 1-adrenoceptor antagonists used in this
study were kindly donated by the following pharmaceutical companies:
doxazosin (Cardura) was obtained from Pfizer (New York, NY); terazosin
(Hytrin) was obtained from Abbott Labs (Chicago, IL); and tamsulosin
(FLOMAX) from Yamanouchi Pharmaceuticals (Tokyo, Japan). The inhibitor,
phenoxybenzamine HCl, was obtained from RBI (Research Biochemicals
International, Natick, MA).
Cell Viability Assay.
Subconfluent cultures of prostate cancer and smooth muscle cells (in
six-well plates) were exposed (in triplicate) to increasing
concentrations of doxazosin, terazosin, or tamsulosin (1–100
µM), and the number of viable cells was assessed after
various treatment periods using the trypan blue exclusion assay. For
the experiment using the irreversible inhibitor, cells were plated in
six-well plates and at 60% density were treated with phenoxybenzamine
(4 h), prior to exposure to increasing doses of 1-adrenoceptor
antagonists. Values are expressed as the percentage of mean cell
viability relative to the untreated cultures.
Rate of DNA Synthesis.
The effect of 1-adrenoceptors on the rate of DNA synthesis in human
prostate cells was evaluated using the
[3
H]thymidine uptake assay. Cells were exposed
to increasing concentrations (1–100 µM) of doxazosin or
terazosin for 2 days and were subsequently pulsed with
[3
H]thymidine (7 µCi/ml) for 4 h. After
DNA precipitation with 10% trichloroacetic acid, the amount of
[3
H]thymidine incorporated was analyzed by
liquid scintillation counting. Values were expressed as the percentage
of inhibition of DNA synthesis in the treated, relative to the
untreated, cultures.
Apoptosis Detection.
Prostate cells were treated with doxazosin or terazosin (15
µM) for 1–3 days, and apoptotic cells were detected
using the TUNEL assay (ApoTag fluorescein kit; Intergen, Purchase, NY).
Cells are visualized using a fluorescence microscope (Axiovert-10 Zeiss
model) and standard fluorescein excitation and emission filters.
Quantitative analysis was performed by counting the green
fluorescence-positive (FITC) cells under x400 magnification.
PARP Assay.
The PARP cleavage assay was used in cell lysates from cell cultures
treated with doxazosin for various treatment periods. Western blot
analysis was performed using a rabbit polyclonal anti-PARP antibody
(Boehringer Mannheim, Indianapolis, IN) and an alkaline phosphatase
detection kit according to the manufacturer’s instructions.
RT-PCR Analysis.
RNA was extracted from prostate cancer cells and human prostate tissue,
and RT-PCR was performed using 1 µg of total cellular RNA and the
Superscript cDNA Preamplification System (Life Technologies, Inc.,
Gaithersburg, MD) in a Perkin-Elmer amplification cycler (Wellesley,
MA) as described previously (17)
. The following primers,
used for 1a-adrenoceptor expression, were obtained from Dr. Paul
Walden (New York University Medical Center, NY): sense,
5'-ATATACCCATGCTCCAGC-3'; antisense, 5'-GCTTTTACTTCTCACCCG-3'. The
primers for the human glyceraldehyde-3-phosphate dehydrogenase were
obtained from Clontech (Palo Alto, CA) and the sequences were as
follows: sense, 5'-TGAAGGRCGGAGTCAACGGATTTGGT-3'; antisense,
5'-CATGTGGGCCATGAGGTCCACCAC-3'. The cycling conditions were the
following: 94°C for 5 min; 94°C for 30 s; 52°C for 1 min;
72°C for 2 min (35 cycles); and 72°C for 7 min (1 cycle) for final
extension. The amplified RT-PCR products were electrophoretically
analyzed through 1% agarose gels and were visualized by ethidium
bromide staining and photographed under UV illumination.
Tumorigenicity Studies.
PC-3 prostate cells were inoculated (106
cells/site) in the flank of male immunodeficient mice (SCID), 4–6
weeks of age, and mice were maintained in a pathogen-free environment.
Tumors were measured twice weekly using a digital caliber, and tumor
volumes were calculated using the formula length x (width)2/2. At 7 days after
implantation, mice were stratified into treatment groups of five
mice/treatment, and treatment began on day -7. Doxazosin mesylate was
administered in the following doses: 0, 3, 10, 100 mg/kg in sterile
water, by oral gavage using a 22-gauge, 1.5-inch gavage needle. Animals
were sacrificed after 2 weeks of treatment.
Statistical Analysis.
In vivo data were analyzed by one-way ANOVA, followed by
pairwise comparison using Fisher’s, Tukey’s, and Dunnetts’s tests
and using the nonparametric test, Kruskal Wallis. Data from in
vitro experiments were analyzed using the Student’s t
test. Values were expressed as the mean ± SE, and
differences were considered statistically significant at
P = 0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The data indicate a significant loss of cell viability of
human prostate cancer cells after 2 days of treatment with doxazosin
and terazosin at concentrations >10 µM.
Tamsulosin had no effect on prostate cancer cell viability (Fig. 1A
). Fig. 1B
documents the dose response of
DU-145 prostate cancer cell viability to the three drugs. Interestingly
enough, only doxazosin exerted a significant cell death effect (70%
loss of cell viability at 25 µM), whereas
terazosin and doxazosin had minimal antigrowth activity (at similar
dose) in this prostate cell line (P > 0.05).
Comparative analysis of the cellular response of the SMC-1 human
prostate smooth muscle cells to doxazosin and terazosin revealed a
relatively high sensitivity of these cells to the antigrowth effects of
both 1-adrenoceptor antagonists in a concentration-dependent manner
(Fig. 1C
).
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, doxazosin treatment resulted in a significant decrease in the rate of
DNA synthesis at high concentrations in a dose dependent-manner in both
cell lines PC-3 and DU-145. After 2 days of exposure to the drug (at
doses of 50 and 100 µM), there was an 
40% inhibition
of the rate of DNA synthesis in both PC-3 and DU-145 cells. Terazosin
and tamsulosin, on the other hand, had no significant effect on the
rate of DNA synthesis in either of the two prostate cancer cell lines
examined at any of the tested doses (Fig. 2
). A comparable profile,
indicating no change in the rate of DNA synthesis in response to all
three 1-adrenoceptor antagonists, was obtained for the prostate
smooth muscle cells SMC-1 (data not shown).
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). Table 1
summarizes the results from the quantitative evaluation of apoptosis
induction in response to doxazosin treatment. A significant increase in
the number of TUNEL-positive apoptotic cells was observed for both
prostate cancer cells and smooth muscle cells after 2 days of treatment
with doxazosin compared with the untreated control cultures. The
apoptotic nature of the effect of doxazosin against prostate cancer
cells was further confirmed by PARP cleavage assay. As shown in Fig. 3B
, exposure of PC-3 prostate cancer cells to doxazosin (15
µM) was associated with cleavage of the PARP
substrate (Mr 115,000 protein) after
24 h of treatment, an effect that became more prominent with
longer treatment periods.
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1a-adrenoceptor mRNA in normal human prostate
tissue and prostate cells was examined by RT-PCR analysis. As shown on
Fig. 4
, there is no detectable mRNA expression for 1a-adrenoceptor in the
two human prostate cancer cells lines PC-3 and DU-145; however,
1a-adrenoceptor mRNA is expressed in the normal human prostate and
cardiac myocytes (used as a positive control; Fig. 4
). Primary cultures
of human smooth muscle cells apparently lose the expression of
1a-adrenoceptor after several passages in
culture.4
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1-adrenoceptors located on the cell membrane and activates
phospholipase, generating a second messenger that ultimately results in
smooth muscle contraction (5)
. To determine whether the
apoptotic effects of doxazosin and terazosin were an 1-mediated
phenomenon, we subsequently tested the ability of an irreversible
1-adrenoceptor inhibitor, phenoxybenzamine, to interfere with the
antigrowth action of the two drugs. Exposure to phenoxybenzamine prior
to treatment did not inhibit the apoptotic effect of doxazosin against
human prostate cancer cells PC-3 (Fig. 5
). Similar observations were obtained for the effect of 1-inhibitor
in terazosin-treated prostate cancer cells (data not shown).
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indicate that breast cancer cells are very sensitive to the
cell death effects of doxazosin, as shown by the significant loss of
cell viability. The magnitude of the cytotoxic effect in these cells
was comparable with that observed in the prostate cancer cell lines. In
contrast, the bladder cancer cells and colon cancer cells exhibited a
moderate sensitivity to both drugs (Fig. 6A
). A similar
cytotoxic profile of the various human cancer cell lines was observed
in response to terazosin treatment (Fig. 6B
), whereas
tamsulosin exerted no detectable effect against any of the cell lines
examined (Fig. 6C
).
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, doxazosin administration in tumor-bearing hosts (via oral gavage; at a
dose of 3 mg/kg) resulted in a notable decrease in the tumor volume of
prostate tumor xenografts compared with the vehicle control-treated
animals (P < 0.5). Interestingly enough,
administration of doxazosin at higher concentrations (10–100 mg/kg)
did not have any further effect on tumor suppression.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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1-adrenoceptor antagonists that are clinically used to provide acute
relief of the obstructive symptoms associated with BPH
(19, 20, 21, 22)
and for the treatment of hypertension
(23)
. The pharmacology of both drugs has been
well-characterized in humans (24
, 25)
, and as a result of
their prolonged use as first-line, once-a-day antihypertensive agents,
their safety profiles have been established. The adverse-effect profile
of these 1-adrenoceptor antagonists is acceptable: by virtue of the
functional involvement of 1-adrenoceptors in the maintenance of
vascular tone, the most frequent side effects include dizziness and
hypotension (26)
.
Targeting apoptosis in an attempt to control prostatic growth emerges
as a potentially powerful therapeutic approach for the effective
treatment of advanced prostate cancer (27)
. The present
study demonstrates that the 1-adrenoceptor antagonists doxazosin and
terazosin (quinazoline derivatives) lead to induction of apoptosis of
human prostate cancer cells and smooth muscle cells in vitro
at intracellular concentrations comparable with the therapeutic
doses.5
Characteristically, the drugs did significantly affect the rate of cell
proliferation. These findings are consistent with our recent clinical
data indicating the ability of doxazosin and terazosin to induce
prostate apoptosis in situ without affecting the
proliferative capacity of prostate cells in BPH patients (14
, 15)
.
Three points of experimental evidence from the present study
support that an 1-adrenoceptor-independent mechanism is involved in
this apoptotic activity: (a) the observation that the
recently introduced, relatively uroselective, 1-blocker tamsulosin
(which is a methoxybenzene sulfonamide) had no effect against prostate
cancer cell growth compared with the other two 1-blockers;
(b) the irreversible 1-adrenoceptor inhibitor
phenoxybenzamine does not inhibit the apoptotic effect of doxazosin or
terazosin against prostate cancer cells; and (c) expression
of 1a-adrenoceptors in human prostate cancer cells is not required,
because the cells lack it, and yet they exhibited sensitivity to the
apoptotic killing of doxazosin and terazosin. The concept that
doxazosin and terazosin suppress prostate growth potentially via
1-adrenoceptor-independent actions gains further support from
another study documenting that doxazosin inhibits proliferation of
human vascular smooth muscle cells independently of an antagonistic
effect on 1-adrenoceptor (28)
. Moreover, our
observations that the apoptotic effect of doxazosin and terazosin was
not exclusively targeted at prostate cells indirectly support this
concept. Interestingly enough, both drugs exerted a similar antigrowth
effect against human MCF-7 breast cancer cells (similar to that
observed in prostate cells) but not against human bladder or colon
cancer cells, implying an action that may selectively be targeted at
hormone-dependent cells.
The in vivo efficacy studies revealed that doxazosin treatment resulted in a significant suppression of tumorigenic growth of the androgen-independent PC-3 prostate cancer xenografts in SCID mice. In accord with these results, the in vivo functional significance of the action of doxazosin has been documented in the mouse reconstitution model of prostate hyperplasia (16) , as well as in long-term reduction of intimal hyperplasia in a rabbit model (29) .
In conclusion, the present study provides the first evidence that
1-adrenoceptor antagonists terazosin and doxazosin, but not
tamsulosin, exert a negative effect on prostatic growth by inducing
apoptosis in both prostate tumor epithelial cells and smooth muscle
cells, an action that is independent of their capacity to antagonize
1-adrenoceptors. On the basis of this evidence and our previous
clinical findings (14
, 15)
, we promote the concept that
induction of prostate apoptosis in response to terazosin and doxazosin
is one of the molecular mechanisms contributing to the overall
long-term clinical profile of both 1-adrenoceptor antagonists in BPH
patients (13)
. Although the potential underlying mechanism
is presently unknown, one may consider that polypeptide growth factors
such as transforming growth factor-ß1, platelet-derived growth
factor, epidermal growth factor, and G-coupled receptor agonists
exhibit substantial overlap in signal transduction mechanisms
(30)
. Doxazosin and terazosin may suppress prostate growth
through deregulation of signal transduction pathways, potentially
involving transforming growth factor-ß signaling or alternatively
perturbations in cell attachment to the extracellular matrix. Studies
are in progress to investigate the mechanistic aspects of the
antigrowth effect of both drugs against prostatic tumors.
The present studies provide a strong rationale for targeting doxazosin and terazosin against prostatic tumors in vivo. Considering that apoptosis induction in prostate biopsies from BPH patients was observed over the normal dose range (14 , 15) , effective clinical application of these drugs, with established safety profiles and already in clinical use for BPH treatment, may result in decreased morbidity in patients with advanced prostate cancer. Long-term, randomized studies involving a large patient population are required to establish the therapeutic significance of doxazosin/terazosin-induced apoptosis in prostate cancer. Once the antigrowth effects of the two medications against advanced human prostate tumors are firmly established, one would expect to demonstrate that in treated patients, there are significant changes of cellular content/prostate size that correlates with increased apoptosis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was partially supported by a
Doxazosin Investigators and Consultants Educational Exchange
award from Pfizer Pharmaceuticals. 
2 To whom requests for reprints should be
addressed, at Division of Urology, Room 8SD, 22 South Greene Street,
University of Maryland Medical Center, Baltimore, MD 21201. Phone:
(410) 706-7549; Fax: (410) 706-0311; E-mail: NKyprianou{at}smail.umaryland.edu
3 The abbreviations used are: BPH, benign
prostatic hypertrophy; RT-PCR, reverse transcription-PCR; SCID, severe
combined immunodeficient; SMC, smooth muscle cell; TUNEL, terminal
deoxynucleotidyl transferase-mediated end labeling; PARP,
poly(ADP-ribose) polymerase.
4 P. Walden, personal communication.
5 N. Kyprianou and M. Wyllie, unpublished data.
Received 1/17/00. Accepted 6/21/00.
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REFERENCES |
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1 adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human 1a subtype. Mol. Pharmacol., 45: 703-708, 1994.[Abstract]
1 adrenergic stimulation and ß2 adrenergic inhibition of DNA synthesis in vascular smooth muscle cells. Mol. Pharmacol., 37: 30-36, 1990.[Abstract]
1-adrenergic antagonist, doxazosin, on noradrenalin-induced modulation of cytoskeletal proteins in cultured hyperplastic prostatic stromal cells. Prostate, 38: 216-227, 1999.[Medline]
1 adrenoceptor subtypes in human prostate. J. Urol., 150: 546-551, 1993.[Medline]
1-Adrenoceptor subtypes in the human prostate. Br. J. Urol., 74: 585-589, 1994.[Medline]
-Adrenergic blockers for the treatment of benign prostatic hyperplasia. Urol. Clin. N. Am., 17: 641-650, 1990.[Medline]
1-Adrenoceptor antagonists terazosin and doxazosin induce prostate apoptosis without affecting cell proliferation in patient with benign prostatic hyperplasia. J. Urol., 161: 2002-2007, 1999.[Medline]
1-adrenergic blocking drugs. Drug Saf., 11: 12-16, 1994.[Medline]
1 adrenergic receptor antagonism. J. Cardiovasc. Pharmacol., 31: 833-839, 1998.[Medline]
1-adrenergic antagonist doxazosin. Br. J. Surg., 79: 1285-1288, 1992.[Medline]
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,
doxazosin; 
, terazosin; 
, tamsulosin.
X174, as a molecular
weight marker. Right, size of the RT-PCR products.
,
PC-3; 
, MCF-7; X, HTB1; 
, SW-480.
, 100 mg/kg doxazosin; 
, 10 mg/kg
doxazosin; 
, 3 mg/kg doxazosin;