**3. Antitumor E**ff**ects of** α**1-Adrenoceptor Antagonists**

Table 1 summarizes the updated evidence from clinical, translational and epidemiological studies, suggesting the antitumor action of α1-adrenoceptor antagonists in human malignancies. The published work from our group and other investigators makes a strong case in support of the repurposing of the α1-adrenoceptor antagonists (with a good safety profile) and advance our current understanding of the clinical value of these therapeutic modalities for the treatment of GU-cancers including renal cancer


#### *3.1. Prostate Cancer*

Based on these pharmacological mechanisms of actions, α1-adrenoceptor antagonists have been shown to have efficacy in the treatment of several genitourinary cancers. There is mounting evidence of the effectiveness of quinazoline-derived α1 blockers in the clinical treatment patients with BPH and prostate tumors. Studies have shown that α1-adrenoceptor antagonists like prozasin and naftopidil inhibit cell growth, arrest cell cycling, decrease microvessel density, and induce apoptosis in human prostate cancer cells [34,35,45]. Doxazosin, a clinically used quinazoline-based α1-adrenoreceptor antagonist, reduced endothelial cell viability and suppressed tumor vascularity in prostate cancer xenografts. The drug additionally exhibited significant antitumor efficacy against models of metastatic castration-resistant prostate cancer (CRPC) [17,30]. In a retrospective observational cohort study at the VA Medical Center in Kentucky, Harris et al. (2007) found that in over a 5-year period in this clinical setting, exposure to quinazoline-based α1-adrenoreceptors antagonists, such as doxazosin and terazosin, significantly decreased the incidence of prostate cancer from 2.4% to 1.65%, corroborating the results of previous investigations [15,45]. While a case-control study of 23,320 men in the Finnish Cancer Registry and national prescription database found tamsulosin and alfuzosin did not improve the odds of developing prostate cancer, the study did discover the drugs significantly decreased the incidence of high-grade tumors in the cohort [47].

More recently, Hart et al. (2020) studied 303 prostate cancer patients to retrospectively determine if α1-blockers influenced response to radiotherapy for localized prostate cancer. The authors found that those treated with prazosin had a 3.9 lower relative risk of biochemical relapse. While not statistically significant, both tamsulosin and prazosin extended survival without recurrence by 13.15 and 9.21 months, respectively [48]. Furthermore, drug optimization efforts led to the development of the quinazoline-derived drug DZ-50. This novel α1 blocker has exerted chemoprotective qualities in vivo in BPH and prostate cancer cells through decreasing angiogenesis and increasing anoikis via inhibition of the TGF-β1 and insulin-like growth factor (IGF) pro-growth pathways [34,35].
