Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of <scp>R</scp>ac, <scp>NSC</scp>23766 and <scp>EHT</scp>1864

Wang, Y; Kunit, Thomas; Ciotkowska, Anna; Rutz, Beata; Schreiber, Andrea; Strittmatter, Frank; Waidelich, Raphaela; Liu, C; Stief, Christian G.; Gratzke, Christian; Hennenberg, Martin

doi:10.1111/bph.13099

Cited by 37 publications

(77 citation statements)

References 57 publications

(96 reference statements)

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“…A major reason could be that the human prostate tissues used in our study are characterized by highly divergent degree of BPH, together with additional overall individual variations, including different content and condition of smooth muscle and different stromal/glandular ratio. This has been demonstrated recently (Kunit et al ., ; Wang et al ., ) and was confirmed again in this study. Thus, adherence to the bare minimum of calculated group sizes instead of flexible design may yield disappointing results in organ bath experiments and may consequently not reflect the reality.…”

Section: Methodssupporting

confidence: 89%

“…Similarly, PSA was detected in almost all prostate samples included to these analyses, with very obvious variations of PSA content between prostates from different patients (Figure B). Together, this may reflect individual variations, and/or different degree of hyperplasia, as recently described (Kunit et al ., ; Wang et al ., ; ,b). Calponin, but not pan‐cytokeratin, was detectable in WPMY‐1 cells (Figure C), confirming the smooth muscle‐like phenotype of these cells (Wang et al ., ).…”

Section: Resultsmentioning

confidence: 99%

“…This requires a more precise understanding of the molecular mechanisms involved in prostate smooth muscle contraction. However, the recent discovery of previously unknown mechanisms demonstrated that prostate smooth muscle contraction is still insufficiently understood (Strittmatter et al ., ; Hennenberg et al ., ; Kunit et al ., ; Wang et al ., ; Wang et al ., ,b). Thus, our present findings may contribute to a better understanding of smooth muscle contraction in the prostate.…”

Section: Discussionmentioning

confidence: 99%

“…Calculations of group sizes for organ bath experiments were carried out using GLIMMPSE (version 2.2.7, http://glimmpse.samplesizeshop.org), an open‐source online tool for calculating power and sample size, on the basis of own previous experimental data (Hennenberg et al ., ; Kreidler et al ., ; Wang et al ., ; ). Calculations were performed separately for each agonist or EFS.…”

Section: Methodsmentioning

confidence: 99%

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Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3

Gratzke

Wang

et al. 2018

British J Pharmacology

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BACKGROUND AND PURPOSEIn men with benign prostatic hyperplasia, increased smooth muscle tone in the prostate may lead to bladder outlet obstruction and subsequent lower urinary tract symptoms. Consequently, medical treatment aims to inhibit prostate smooth muscle contraction. However, the efficacy of the treatment options available is limited, and improved understanding of mechanisms of prostate smooth muscle contraction and identification of new targets for medical intervention are mandatory. Several studies suggest that LIM kinases (LIMKs) promote smooth muscle contraction; however, this has not yet been examined. Here, we studied effects of the LIMK inhibitors on prostate smooth muscle contraction. EXPERIMENTAL APPROACHHuman prostate tissues were obtained from radical prostatectomy. Phosphorylation of cofilin, a LIMK substrate, was examined using a phospho-specific antibody. Smooth muscle contractions were studied in organ bath experiments. KEY RESULTSReal-time PCR, Western blot and immunofluorescence suggested LIMKs are expressed in smooth muscle cells of prostate tissues. Two different LIMK inhibitors, SR7826 (1 μM) and LIMKi3 (1 μM), inhibited contractions of prostate strips, which were induced by electrical field stimulation, α 1 -adrenoceptor agonists phenylephrine and methoxamine and the TXA 2 analogue, U46619. LIMK inhibition in prostate tissues and cultured stromal cells (WPMY-1) was confirmed by cofilin phosphorylation, which was reduced by SR7826 and LIMKi3. In WPMY-1 cells, SR7826 and LIMKi3 caused breakdown of actin filaments and reduced viability. CONCLUSIONS AND IMPLICATIONSSmooth muscle tone in the hyperplastic human prostate may underlie the effects of LIMKs, which promote contraction. Contraction of prostate strips can be inhibited by small molecule LIMK inhibitors.

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Section: Methodssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3

Gratzke

Wang

et al. 2018

British J Pharmacology

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“…Moreover, combination therapies are required to target smooth muscle contraction and growth in the prostate at once (Oelke et al, ; Hennenberg et al, ). Recent progress from basic research provided rising evidence for possible relationships between the control of smooth muscle tone and regulation of stromal growth in the human prostate (Wang et al, ). On the basis of our present findings, a connection between contraction and growth in the prostate may be assumed, being accomplished by SFKs.…”

Section: Discussionmentioning

confidence: 99%

Smooth muscle contraction and growth of stromal cells in the human prostate are both inhibited by the Src family kinase inhibitors, AZM475271 and PP2

Wang

Gratzke

Tamalunas

et al. 2016

British J Pharmacology

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Background and Purpose In benign prostatic hyperplasia, increased prostate smooth muscle tone and prostate volume may contribute alone or together to urethral obstruction and voiding symptoms. Consequently, it is assumed there is a connection between smooth muscle tone and growth in the prostate, but any molecular basis for this is poorly understood. Here, we examined effects of Src family kinase (SFK) inhibitors on prostate contraction and growth of stromal cells. Experimental Approach SFK inhibitors, AZM475271 and PP2, were applied to human prostate tissues to assess effects on smooth muscle contraction, and to cultured stromal (WPMY‐1) and c‐Src‐deficient cells to examine effects on proliferation, actin organization and viability. Key Results SFKs were detected by real time PCR, western blot and immunofluorescence in human prostate tissues, some being located to smooth muscle cells. AZM475271 (10 μM) and PP2 (10 μM) inhibited SFK in prostate tissues and WPMY‐1 cells. Both inhibitors reduced α1‐adrenoceptor‐mediated and neurogenic contraction of prostate strips. This may result from cytoskeletal deorganization, which was observed in response to AZM475271 and PP2 in WPMY‐1 cells by staining of actin filaments with phalloidin. This was paralleled by reduced proliferation of wildtype but not of c‐Src‐deficient cells; cytotoxicity was mainly observed at higher concentrations (>50 μM). Conclusions and Implications In human prostate, smooth muscle tone and growth are both controlled by an SFK‐dependent process, which may explain their common role in bladder outlet obstruction. Targeting prostate smooth muscle tone and prostate growth simultaneously by a single compound may, in principal, be possible.

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Inhibition of Adrenergic and Non-Adrenergic Smooth Muscle Contraction in the Human Prostate by the Phosphodiesterase 10-Selective Inhibitor TC-E 5005

et al. 2016

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Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of Rac, NSC23766 and EHT1864

Abstract: Rac may be a link connecting the control of prostate smooth muscle tone with proliferation of smooth muscle cells. Improvements in LUTS suggestive of BPH by Rac inhibitors appears possible.

Cited by 37 publications

References 57 publications

Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3

Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3

Smooth muscle contraction and growth of stromal cells in the human prostate are both inhibited by the Src family kinase inhibitors, AZM475271 and PP2

Inhibition of Adrenergic and Non-Adrenergic Smooth Muscle Contraction in the Human Prostate by the Phosphodiesterase 10-Selective Inhibitor TC-E 5005

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