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The role of α1-adrenoceptor antagonists in the treatment of prostate and other cancers
Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin;
Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M; Spencer,
Briohny; Christie, David; Chess-Williams, Russ
Published in:
International Journal of Molecular Sciences
DOI:
10.3390/ijms17081339
Licence:
CC BY
Link to output in Bond University research repository.
Recommended citation(APA):
Batty, M., Pugh, R., Rathinam, I., Simmonds, J., Walker, E., Forbes, A., Anoopkumar-Dukie, S., McDermott, C.
M., Spencer, B., Christie, D., & Chess-Williams, R. (2016). The role of α1-adrenoceptor antagonists in the
treatment of prostate and other cancers.
International Journal of Molecular Sciences
,
17
(8), 1-26. [1339].
https://doi.org/10.3390/ijms17081339
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Download date: 26 Aug 2022
International Journal of
Molecular Sciences
Review
The Role of α1-Adrenoceptor Antagonists in the
Treatment of Prostate and Other Cancers
Mallory Batty
1,†
, Rachel Pugh
1,†
, Ilampirai Rathinam
1,†
, Joshua Simmonds
1,†
,
Edwin Walker
1,†
, Amanda Forbes
2,†
, Shailendra Anoopkumar-Dukie
1,3
,
Catherine M. McDermott
2
, Briohny Spencer
1
, David Christie
1,2
and Russ Chess-Williams
2,
*
1
School of Pharmacy, Griffith University, Gold Coast, QLD 4222, Australia;
mallory.batty@griffithuni.edu.au (M.B.); rachel.pugh@griffithuni.edu.au (R.P.);
ilampirai.rathinam@griffithuni.edu.au (I.R.); joshua.simmonds@griffithuni.edu.au (J.S.);
edwin.walker@griffithuni.edu.au (E.W.); s.dukie@griffith.edu.au (S.A.-D.); b.spencer@griffith.edu.au (B.S.);
David.Christie@genesiscare.com.au (D.C.)
2
Centre for Urology Research, Faculty of Health Sciences and Medicine, Bond University, Robina, QLD 4226,
Australia; amanda.forbes@student.bond.edu.au (A.F.); camcderm@bond.edu.au (C.M.M.)
3
Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia
* Correspondence: rchesswi@bond.edu.au; Tel.: +61-7-5595-4420
† These authors contributed equally to this work.
Academic Editor: William Chi-shing Cho
Received: 6 July 2016; Accepted: 8 August 2016; Published: 16 August 2016
Abstract:
This review evaluates the role of
α
-adrenoceptor antagonists as a potential treatment of
prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two
articles for analysis.
In vitro
studies demonstrate that doxazosin, prazosin and terazosin (quinazoline
α
-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145
cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9
cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects.
In vivo
data was
consistent with
in vitro
findings as the quinazoline based
α
-antagonists prevented angiogenesis and
decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects
of the
α
-antagonists appear largely independent of
α
1-blockade. The proposed targets include:
VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing
factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data
is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to
α
-antagonists. As human data evaluating the use of
α
-antagonists as treatments are lacking; well
designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties
of quinazoline based α-antagonists in PCa and other cancers.
Keywords: α1-adrenoceptor antagonist; prostate cancer; cytotoxicity
1. Introduction
Prostate cancer is the most commonly diagnosed male cancer in the world [
1
]. In Australia,
prostate cancer account for approximately 30% of all newly diagnosed cancers and is the second most
common cause of cancer-specific death in men [
2
]. Early stage prostate cancer is highly manageable
using definitive radical prostatectomy and/or radiotherapy techniques. However, an estimated
one-fifth of men will experience disease recurrence following curative treatment modalities [
3
–
5
]
and resort to first-generation androgen deprivation therapies for long-term management of their
disease. Unfortunately, progression after androgen deprivation therapy indicates the transition to
castrate-resistant prostate cancer (CRPC), which is considered to be both inevitable and incurable.
Although there has been significant progress in the CRPC treatment landscape (e.g., enzalutamide,
Int. J. Mol. Sci. 2016, 17, 1339; doi:10.3390/ijms17081339 www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2016, 17, 1339 2 of 25
abiraterone, cabazitaxel), there are no currently available therapies which provide a survival benefit
greater than twelve months [
6
–
10
]. Therefore, there is an urgent need for novel agents to improve the
oncological and survival outcomes for these last-resort patients. One such modality may be through
the use of α1-adrenoceptor (ADR) antagonists.
Adrenoceptors (also known as adrenergic receptors) are members of the G protein-coupled
receptor (GPCR) superfamily, which can be further broken down into
α
and
β
subtypes with several
homologous isoforms including
α
-1 (A, B, and D), -2 (A, B, and C), and
β
-1, 2, and 3 [
11
]. While
all adrenergic receptors play an important role in regulating human tissue homeostasis, the focus of
this review will primarily cover
α
1-ADRs in the human prostate.
α
1-ADRs are largely found in the
stromal region of the human prostate, with few
α
1-ADR receptors localised in the prostate epithelium.
Although, the
α
1A-ADR isoform (previously identified as
α
1C) is known to make up approximately
70% of the prostatic
α
1-ADRs [
12
], recent evidence suggests that the distribution of
α
1-ADR isoforms
(A, B and D) change with advancing age and are correlated with the subsequent onset of prostatic
hyperplasia [
13
]. Likewise, receptor localisation and expression appears to be altered in prostate
cancer tissues. Unlike normal prostate epithelium which expresses few
α
1-ADRs, prostate cancer
epithelia have been reported to express functional
α
1A-ADR [
14
,
15
], as well as increased mRNA levels
of
α
1B and
α
1D isoforms [
16
]. It remains unclear whether
α
1-ADRs have a role in promoting prostate
carcinogenesis remains unclear. However,
α
1-ADRs have been identified to play a role in cellular
proliferation in vitro [14,17–19] and therefore may be exploited for treatment of neoplasms.
α
1-ADR antagonists (referred to here as “
α
-antagonists”) are commonly used in clinical practice
to treat hypertension, and more recently, the urodynamic symptoms associated with benign prostate
hyperplasia (BPH). In BPH,
α
-antagonists block receptor activation to relax the prostatic smooth muscle
thereby improving rate of urine flow and other associated lower-urinary tract symptoms (LUTS) [
20
,
21
].
There are regional differences in the commonly prescribed
α
-antagonists for BPH. In the United States,
the non-selective doxazosin and terazosin are the most commonly prescribed
α
1-blockers due to
their relatively long half-life [
22
,
23
] and clinically significant improvement in BPH-related LUTS.
Furthermore, these drugs have been associated with fewer adverse drug-related cardiovascular side
effects, compared to prazosin [
24
]. However, in Australia, the short acting and non-selective prazosin
is clinically favored over other
α
-antagonists primarily due to the rapid mitigation of LUTS. The highly
selective tamulosin, also offer significant reduction in BPH-related LUTS symptoms, however, at a cost
of ejaculatory dysfunction making this α1-ADR antagonists undesirable for some men [24].
In the late 1990s, monotherapy with
α
-antagonists was shown to provide long-term clinical
benefits that could not be explained solely by acute prostatic relaxation [
25
–
27
]. In support of these
findings, a more recent study uncovered a large proportion of men (70%) experienced continued
improvement of BPH-associated LUTS following discontinuation of
α
-antagonists [
28
]. Subsequent
studies over the next sixteen years have identified that some of these drugs possess novel cytotoxic
actions in diseased prostates, including prostate and other cancers. Despite the plethora of original
papers investigating the anticancer effects of these drugs, only few systematic reviews since the early
2000s have been carried out to colligate the more recent published findings [
29
–
33
]. Therefore, the
aim of this systematic literature review is to analyse the current evidence for the use of
α
-antagonists
as potential treatment options for prostate cancer (PCa). Specifically, this review will colligate the
anticancer mechanisms of
α
-antagonists, evaluate the evidence supporting clinical anticancer efficacy
of these drugs in PCa, and evaluate the evidence for use of these drugs in other cancers.
2. Results
Pubmed, Google Scholar and Cochrane databases were accessed to retrieve articles. The search
terms used to find the relevant articles were separated into three categories: terms that describe the
α
-antagonists, the target tissue and the action of the drugs (Table A1). Four hundred and ninety-six
articles were identified using the inclusion criteria by searching three databases: Cochrane, Pubmed
and Google Scholar. After exclusion criteria were applied, sixty-two relevant articles were obtained,
Int. J. Mol. Sci. 2016, 17, 1339 3 of 25
consisting of fifty-four original manuscripts and eight review articles. (Figure A1). Of the fifty-four
research articles identified only four studies examined the role of
α
-antagonists in PCa development in
humans (Table 1). The majority focused on the cytotoxic and anti-tumour activity of
α
-antagonists
in vitro
and in animal models (Table 2). These retrospective cohort and observational human studies
examined the effects of both quinazoline and non-quinazoline
α
-antagonists, but show only an overall
decreased incidence of PCa. Two additional researchers replicated the search which returned identical
results, validating the method used, for robustness.
Int. J. Mol. Sci. 2016, 17, 1339 4 of 25
Table 1. Clinical-based studies investigating the effect of α1-antagonists on prostate cancer (PCa).
Author Title Drug Results Study Type
Keledjian, K. et al. [34]
Reduction of human prostate tumor
vascularity by the α1-adrenoceptor
antagonist terazosin
Terazosin
Increased apoptotic index in prostate carcinoma after terazosin treatment.
Reduction in prostate tumour vascularity in terazosin-treated BPH patients.
Patients were treated for 6–11 months
Retrospective Cohort study
Harris, A. et al. [35]
Effect of α1-adrenoceptor antagonist
exposure on prostate cancer incidence:
an observational cohort study
Doxazosin & Terazosin
4070 men were treated with
α
-antagonists for Benign prostatic hyperplasia
or hypertension or HTN. The incidence of PCa among treated men vs.
untreated men was 1.65% and 2.41% respectively. Data showed 7.6 fewer
cases developed per 1000 exposed men
Observational Cohort study
Yamada, D. et al. [36]
Reduction of prostate cancer incidence by
naftopidil, an α1-adrenoceptor
antagonist and transforming growth
factor-β signalling inhibitor
Naftopidil & Tamsulosin
PCa incidence was significantly lower in men treated with naftopidil for
≥3 months compared to men treated with tamsulosin. (p = 0.035)
Retrospective Cohort study
Bilbro, J. et al. [37]
Therapeutic value of quinazoline-based
compounds in prostate cancer
Doxazosin, terazosin and
other quinazolines
Patients treated with α
1
-antagonists: doxazosin and terazosin, at the
Markey Cancer centre had reduced risk of developing PCa
Retrospective Cohort study
Table 2. Summary of identified studies investigating the anticancer effect of α-antagonists.
Ref. Author Title Study Type Cancer Type Drugs Findings (Original Studies)
[29] Nishizaki, T. et al.
1-[2-(2-Methoxyphenylamino)
ethylamino]-3-(naphthalene-1-yloxy)
propan-2-ol may be a promising
anticancer drug
Review NA NA
[30] Kyprianou, N. et al.
Apoptosis induction by doxazosin
and other quinazoline
α1-adrenoceptor antagonists: a new
mechanism for cancer treatment?
Review NA NA
[31] Patane, S. et al.
Insights into cardio-oncology:
Polypharmacology of
quinazoline-based
α1-adrenoceptor antagonists
Review NA NA
[32] Desiniotis, A. et al.
Advances in the design and
synthesis of prazosin derivatives
over the last ten years
Review NA NA
[33]
Tahmatzopoulos, A.
et al.
The role of α-blockers in the
management of prostate cancer
Review NA NA