Piperazine-Derived α(1D/1A) Antagonist 1- Benzyl-N- (3-(4- (2-Methoxyphenyl) Piperazine-1-yl) Propyl) -1H- Indole-2- Carboxamide Induces Apoptosis in Benign Prostatic Hyperplasia Independently of α1-Adrenoceptor Blocking.
Piperazine-Derived α(1D/1A) Antagonist 1- Benzyl-N- (3-(4- (2-Methoxyphenyl) Piperazine-1-yl) Propyl) -1H- Indole-2- Carboxamide Induces Apoptosis in Benign Prostatic Hyperplasia Independently of α1-Adrenoceptor Blocking.
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哌嗪衍生的 α(1D/1A) 拮抗剂 1-苄基-N-(3-(4-(2-甲氧基苯基)哌嗪-1-基)丙基)-1H-吲哚-2-甲酰胺独立诱导良性前列腺增生细胞凋亡
DOI：
10.3389/fphar.2020.594038
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发表时间：
2020
影响因子：
5.6
通讯作者：
Huang JJ
中科院分区：
文献类型：
--
作者：
Xiao Q;Liu QM;Jiang RC;Chen KF;Zhu X;Ma L;Li WX;He F;Huang JJ
前期研究表明α1D/1A拮抗剂萘托地尔（naftopidil， NAF）在良性前列腺增生（BPH）中通过降低细胞增殖抑制前列腺生长，而不影响细胞凋亡和前列腺体积。我们实验室报道了一种naff衍生的α1D/1A拮抗剂1-苄基- n -(3-（4-（2-甲氧基苯基）哌嗪-1-基）- 1h -吲哚-2- carboxamide (HJZ-12)，该拮抗剂对α1D-和α1A- AR均表现出高亚型选择性（分别为α 1b -AR的47.9倍和19.1倍）。然而，没有进行进一步的研究。本研究通过雌激素/雄激素诱导的大鼠BPH模型和人BPH-1细胞系对HJZ-12在BPH中的药理作用进行了评价。在体内，HJZ-12在抑制大鼠前列腺增生方面表现出比NAF更好的效果，不仅能减少前列腺重量和增生（与NAF相似），还能缩小前列腺体积和诱导前列腺凋亡（与NAF不同）。在体外，HJZ-12对BPH-1细胞株表现出明显的细胞活力抑制和凋亡诱导作用，但不表现出细胞抗增殖作用。有趣的是，HJZ-12对细胞活力和凋亡的作用是不依赖于α1的。此外，应用RNA-Seq分析筛选6个抗凋亡基因（Bcl-3、b -淋巴瘤Mo-MLV插入区1 [Bmi-1]、ITGA2、FGFR3、RRS1和SGK1）。其中，Bmi-1参与了BPH-1中HJZ-12的凋亡诱导。综上所示，HJZ-12通过α -1不依赖的凋亡诱导，在阻止前列腺增生的进展中发挥了显著的作用，表明它将是治疗BPH的多靶点有效候选者。
Previous studies have indicated that α1D/1A antagonist naftopidil (NAF) suppresses prostate growth by decreasing cell proliferation without affecting apoptosis and prostate volume in benign prostatic hyperplasia (BPH). A NAF-derived α1D/1A antagonist 1- benzyl-N-(3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl)-1H-indole-2- carboxamide (HJZ-12) has been reported from our laboratory, which exhibits high subtype-selectivity to both α1D- and α1A- AR (47.9- and 19.1- fold, respectively) with respect to a1B-AR in vitro. However, no further study was conducted. In the present study, a pharmacological evaluation of HJZ-12 in BPH was performed on an estrogen/androgen-induced rat BPH model and human BPH-1 cell line. In vivo, HJZ-12 exhibited better performance than NAF in preventing the progression of rat prostatic hyperplasia by not only decreasing prostate weight and proliferation (similar to NAF) but also, shrinking prostate volume and inducing prostate apoptosis (different from NAF). In vitro, HJZ-12 exhibited significant cell viability inhibition and apoptotic induction in BPH-1 cell line, without presenting cell anti-proliferation properties. Intriguingly, the role of HJZ-12 on cell viability and apoptosis was an α1-independent action. Furthermore, RNA-Seq analysis was applied to screen out six anti-apoptotic genes (Bcl-3, B-lymphoma Mo-MLV insertion region 1 [Bmi-1], ITGA2, FGFR3, RRS1, and SGK1). Amongst them, Bmi-1 was involved in the apoptotic induction of HJZ-12 in BPH-1. Overall, HJZ-12 played a remarkable role in preventing the progression of prostatic hyperplasia through α1-independent apoptotic induction, indicating that it will be a multi-target effective candidate for BPH treatment.
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影响因子：
3.3
作者：
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通讯作者：
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影响因子：
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6.6
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影响因子：
9
作者：
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