We recently demonstrated that
silodosin, a selective α1-blocker often prescribed for the symptomatic treatment of
benign prostatic hyperplasia (BPH), could inactivate a c-fos proto-oncogene regulator ELK1 in
bladder cancer cells possessing a functional
androgen receptor (AR). However, the clinical impact of α1-blockers on the development and progression of
bladder cancer remained poorly understood. In the present study, we investigated if α1-blockers clinically used, including
silodosin,
tamsulosin, and
naftopidil, could prevent the neoplastic/malignant transformation and cell growth, using non-neoplastic urothelial SVHUC sublines with
carcinogen/MCA challenge and
bladder cancer lines, respectively.
Bladder cancers in men treated with
silodosin,
tamsulosin, or
naftopidil for their BPH were then compared.
Silodosin at 1-10 µM significantly inhibited the neoplastic transformation of MCA-SVHUC-AR cells, but not that of AR-negative MCA-SVHUC-control cells. In MCA-SVHUC-AR,
silodosin significantly reduced the expression levels of oncogenes (c-fos/NF-κB1) and induced those of
tumor suppressors (p27/PTEN). However,
tamsulosin (up to 1 µM) or
naftopidil (up to 10 µM) failed to significantly inhibit the neoplastic transformation of AR-positive or AR-negative urothelial cells. Similarly, cell proliferation/migration of AR-positive
bladder cancer lines was considerably inhibited only by
silodosin. Meanwhile, the incidence of
bladder cancer in patients with
silodosin [49/540 (9.1%)] was marginally lower, compared to those with
tamsulosin [64/523 (12.2%); P=0.094] or
tamsulosin or
naftopidil [64+28/523+236 (12.1%); P=0.082]. There were no significant differences in
tumor grade/stage among the 3 cohorts. Outcome analysis revealed lower risks for
disease progression of non-muscle-invasive
bladder tumors in the
silodosin group than in the
naftopidil group (P=0.011) or tamsulosin+naftopidil groups (P=0.035). Similarly,
silodosin patients with muscle-invasive
tumor had lower risks for
disease progression, compared with
tamsulosin (P=0.006) or tamsulosin+naftopidil (P=0.028) patients. Multivariate analysis further showed that
silodosin treatment in those with non-muscle-invasive
tumor was associated with improved progression-free survival, compared with
naftopidil (hazard ratio=0.086; 95% confidence interval=0.008-0.905; P=0.041) or
tamsulosin/
naftopidil (hazard ratio=0.128; 95% confidence interval=0.016-1.036; P=0.054) treatment. Our in vitro studies thus indicate that both urothelial
tumorigenesis and
tumor growth are inhibited by
silodosin, but not by
tamsulosin or
naftopidil. Clinical data further suggest that even pharmacological doses (e.g. 0.1 µM) of
silodosin contribute to preventing
bladder cancer progression.