Abstract
Prostate smooth muscle tone and hyperplastic growth are involved in the pathophysiology and treatment of male lower urinary tract symptoms (LUTS). Available drugs are characterized by limited efficacy. Patients’ adherence is particularly low to combination therapies of 5α-reductase inhibitors and α1-adrenoceptor antagonists, which are supposed to target contraction and growth simultaneously. Consequently, molecular etiology of benign prostatic hyperplasia (BPH) and new compounds interfering with smooth muscle contraction or growth in the prostate are of high interest. Here, we studied effects of p21-activated kinase (PAK) inhibitors (FRAX486, IPA3) in hyperplastic human prostate tissues, and in stromal cells (WPMY-1). In hyperplastic prostate tissues, PAK1, -2, -4, and -6 may be constitutively expressed in catecholaminergic neurons, while PAK1 was detected in smooth muscle and WPMY-1 cells. Neurogenic contractions of prostate strips by electric field stimulation were significantly inhibited by high concentrations of FRAX486 (30 μM) or IPA3 (300 μM), while noradrenaline- and phenylephrine-induced contractions were not affected. FRAX486 (30 μM) inhibited endothelin-1- and -2-induced contractions. In WPMY-1 cells, FRAX486 or IPA3 (24 h) induced concentration-dependent (1–10 μM) degeneration of actin filaments. This was paralleled by attenuation of proliferation rate, being observed from 1 to 10 μM FRAX486 or IPA3. Cytotoxicity of FRAX486 and IPA3 in WPMY-1 cells was time- and concentration-dependent. Stimulation of WPMY-1 cells with endothelin-1 or dihydrotestosterone, but not noradrenaline induced PAK phosphorylation, indicating PAK activation by endothelin-1. Thus, PAK inhibitors may inhibit neurogenic and endothelin-induced smooth muscle contractions in the hyperplastic human prostate, and growth of stromal cells. Targeting prostate smooth muscle contraction and stromal growth at once by a single compound is principally possible, at least under experimental conditions.
Highlights
Patients with benign prostatic hyperplasia (BPH) are often characterized by voiding symptoms, caused by bladder outlet obstruction (BOO) due to abnormal prostate smooth muscle tone and prostate enlargement [1,2,3]
As any effect on proliferation of prostate cells may be interesting for application in BPH, where hyperplastic growth induces symptoms, we examined effects of p21-activated kinase (PAK) inhibitors on proliferation of WPMY-1 cells
We are aware that any efficacy of PAK inhibitors for improvement of lower urinary tract symptoms (LUTS) needs to be confirmed in vivo, and that applications may be limited by side-effects
Summary
Patients with benign prostatic hyperplasia (BPH) are often characterized by voiding symptoms, caused by bladder outlet obstruction (BOO) due to abnormal prostate smooth muscle tone and prostate enlargement [1,2,3]. Smooth muscle contraction in the prostate is induced by activation of α1-adrenoceptors, while hyperplastic growth is triggered by dihydrotestosteron [2, 3]. Limitations of α1-blockers may be explained by contributions of non-adrenergic mediators, which may induce prostate smooth muscle contraction even in the presence of α1-blockers [2]. Such non-adrenergic mediators, which increase prostate smooth muscle tone in parallel to α1adrenoceptors, include endothelins and thromboxane A2 [2]. An ideal medication for treatment of voiding symptoms would address adrenergic and non-adrenergic smooth muscle contraction, plus prostate growth at once. A possible context between smooth muscle contraction and growth in the hyperplastic prostate has been assumed, but underlying molecular mechanisms are poorly understood [2, 5]
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