PDF(Pubmed)
Abstract：
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.
摘要：
我们最近证明了西洛多辛，通常用于良性前列腺增生（BPH）对症治疗的选择性α1受体阻滞剂，可以使具有功能性雄激素受体（AR）的膀胱癌细胞中的c-fos原癌基因调节因子ELK1失活。然而,α1-受体阻滞剂对膀胱癌发展和进展的临床影响仍然知之甚少.在本研究中,我们调查了临床上是否使用α1-受体阻滞剂，包括西洛多辛,坦索罗辛,还有naftopidil,可以防止肿瘤/恶性转化和细胞生长，使用具有致癌物/MCA攻击的非肿瘤尿路上皮SVHUC亚系和膀胱癌系，分别。用西洛多辛治疗的男性膀胱癌，坦索罗辛,然后比较了他们的BPH或萘哌地尔。1-10µM的Silodosin显着抑制MCA-SVHUC-AR细胞的肿瘤转化，但不是AR阴性MCA-SVHUC对照细胞。在MCA-SVHUC-AR中，silodosin显着降低了癌基因（c-fos/NF-κB1）的表达水平，并诱导了肿瘤抑制因子（p27/PTEN）的表达水平。然而,坦索罗辛（高达1µM）或萘哌地尔（高达10µM）不能显着抑制AR阳性或AR阴性尿路上皮细胞的肿瘤转化。同样，AR阳性膀胱癌细胞系的细胞增殖/迁移仅被silodosin抑制。同时,西洛多辛患者的膀胱癌发病率[49/540（9.1％）]略低，与坦索罗辛[64/523(12.2%);P=0.094]或坦索罗辛或萘哌地尔[64+28/523+236(12.1%);P=0.082]相比。3个队列中的肿瘤分级/分期没有显著差异。结果分析显示，与萘哌地尔组(P=0.011)或坦索罗辛+萘哌地尔组(P=0.035)相比，西洛多辛组非肌肉浸润性膀胱肿瘤疾病进展风险较低。同样，患有肌肉浸润性肿瘤的西洛多辛患者疾病进展的风险较低，与坦索罗辛(P=0.006)或坦索罗辛+萘哌地尔(P=0.028)患者比较。多变量分析进一步显示，在非肌肉浸润性肿瘤患者中，西洛多辛治疗与无进展生存期改善相关。与萘哌地尔(风险比=0.086;95%置信区间=0.008-0.905;P=0.041)或坦索罗辛/萘哌地尔(风险比=0.128;95%置信区间=0.016-1.036;P=0.054)治疗比较.因此，我们的体外研究表明，尿路上皮肿瘤发生和肿瘤生长都受到西洛多辛的抑制，但不是坦索罗辛或萘哌地尔。临床数据进一步表明，即使药理学剂量（例如0.1μM）的西洛多辛也有助于预防膀胱癌进展。
