BXL‐628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA/Rho kinase signaling in rat and human bladder

Morelli, Annamaria; Vignozzi, Linda; Filippi, Sandra; Vannelli, Gabriella Barbara; Ambrosini, Stefano; Mancina, Rosa; Crescioli, Clara; Donati, Silvia; Fibbi, Benedetta; Colli, Enrico; Adorini, Luciano; Maggi, Mario

doi:10.1002/pros.20463

Cited by 70 publications

(120 citation statements)

References 45 publications

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“…However, the present study demonstrated that 1,25-(OH) 2 D 3 acts as an inhibitor of RhoA/ROCK and its role may depend on cell types. In accordance with the results of the present study, it has previously been demonstrated that BXL-628 is able to inhibit RhoA activation in a dose-dependent manner without altering RhoA expression, and ameliorates excessive hyperplasia and aberrant differentiation in bladder smooth muscle cells (24,25). In the present study, 1,25-(OH) 2 D 3 exerted a similar effect to BXL-628 at a much higher concentration.…”

Section: Discussionsupporting

confidence: 92%

“…This suggests that BXL-626 may be a more efficient pharmaceutical choice, although further beneficial value must be investigated through more clinical studies and fundamental research. 1,25-(OH) 2 D 3 and BXL-628 do not alter the expression of RhoA and ROCK, however they do increase their membrane translocation and binding to GTP (24,35).…”

Section: Discussionmentioning

confidence: 87%

“…Morelli et al (24) illustrated that treatment with elocalcitol (BXL-628), which is a VitD analog and VDR agonist, impaired RhoA membrane translocation and inhibited RhoA/ROCK activation in bladder smooth muscle cells, repressing RhoA-mediated cell migration and cytoskeleton remodeling (24,25). However, whether the anti-EMT and anti-fibrosis role of 1,25-(OH) 2 D 3 and analogs is associated with the RhoA/ROCK signaling pathway remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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1,25-(OH)2D3 and its analogue BXL-628 inhibit high glucose-induced activation of RhoA/ROCK pathway in HK-2 cells

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. It has previously been reported that 1,25-(OH) 2 D 3 inhibits high glucose-induced epithelial-to-mesenchymal transition (EMT) in HK-2 cells. However, the mechanism of this renoprotective action remains unclear. Elocalcitol (BXL-628), a vitamin D analog, has been suggested to be effective on the RhoA/Rho associated protein kinase (ROCK) pathway, which serves a crucial role in high glucose-induced EMT. The aim of the present study was to investigate the effect of 1,25-(OH) 2 D 3 and its analogue BXL-628 on high glucose-induced activation of the RhoA/ROCK pathway in human renal proximal tubular cells. HK-2 cells were co-treated with high glucose and either 1,25-(OH)2D3 or BXL-628. The RhoA expression levels and ROCK activity of the membrane were assessed via western blot analysis or immunofluorescence. α-smooth muscle actin (α-SMA) and epithelial (E)-cadherin were detected using western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), whereas collagen I and fibronectin levels were measured by ELISA and RT-qPCR. The results demonstrated that 1,25-(OH) 2 D 3 and BXL-628 both significantly downregulated the expression of active RhoA and ROCK activity induced by high glucose (P<0.05). Furthermore, the expressions of α-SMA, collagen I, and fibronectin were significantly downregulated at both protein and mRNA (P<0.05) levels, whereas the expression of E-cadherin was significantly increased (P<0.05) by 1,25-(OH) 2 D 3 or BXL-628 treatment. In conclusion, the vitamin D receptor agonist 1,25-(OH) 2 D 3 and its analogue BXL-628 were both able to attenuate high glucose-induced EMT and extracellular matrix accumulation of HK-2 cells by suppressing the RhoA/ROCK signaling pathway in vitro.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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1,25-(OH)2D3 and its analogue BXL-628 inhibit high glucose-induced activation of RhoA/ROCK pathway in HK-2 cells

Zhang

et al. 2017

Experimental and Therapeutic Medicine

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“…Indications supporting this possibility could be obtained by functional analysis, for example by evaluating nerve-induced and frequency-dependent contractile responses in isolated prostates. EAP-induced changes of the Rho kinase pathway might also be involved in altered regulation of emission in NOD mice, and this pathway could be inhibited by Elocalcitol treatment, as recently shown in the bladder of spontaneously hypertensive rats (55). Therapeutic administration of Elocalcitol in NOD mice with established EAP decreases IFN-␥ production by anti-TCR-stimulated lymph node cells, indicating inhibition of Th1 cell responses in prostate-draining periaortic lymph nodes.…”

Section: Discussionmentioning

confidence: 58%

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

Penna

Amuchastegui

Cossetti

et al. 2006

The Journal of Immunology

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On the basis of on the marked inhibitory activity of the vitamin D receptor agonist Elocalcitol on basal and growth factor-induced proliferation of human prostate cells and on its potent anti-inflammatory properties, we have tested its capacity to treat experimental autoimmune prostatitis (EAP) induced by injection of prostate homogenate-CFA in nonobese diabetic (NOD) mice. Administration of Elocalcitol, at normocalcemic doses, for 2 wk in already established EAP significantly inhibits the intraprostatic cell infiltrate, leading to a profound reduction in the number of CD4+ and CD8+ T cells, B cells, macrophages, dendritic cells, and I-Ag7-positive cells. Immunohistological analysis demonstrates reduced cell proliferation and increased apoptosis of resident and infiltrating cells. Significantly decreased production of the proinflammatory cytokines IFN-γ and IL-17 is observed in prostate-draining lymph node T cells from Elocalcitol-treated NOD mice stimulated by TCR ligation. In addition, Elocalcitol treatment reduces IFN-γ production by prostate-infiltrating CD4+ T cells and draining lymph node T cells specific for an immunodominant peptide naturally processed from prostate steroid-binding protein, a prostate-specific autoantigen. Finally, CD4+ splenic T cells from Elocalcitol-treated NOD mice show decreased ability, upon adoptive transfer into NOD.SCID recipients, to induce autoimmune prostatitis, paralleled by a reduced capacity to produce IFN-γ in response to prostate steroid-binding protein. The results indicate that Elocalcitol is able to interfere with key pathogenic events in already established EAP in the NOD mouse. These data show a novel indication for vitamin D receptor agonists and indicate that treatment with Elocalcitol may inhibit the intraprostatic inflammatory response in chronic prostatitis/chronic pelvic pain syndrome patients.

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“…Analogues of vitamin D 3 have been shown to inhibit BPH cell proliferation and to counteract the mitogenic activity of potent growth factors for BPH cells [Crescioli et al 2004;. However, elocalcitol was also shown to have an inhibitory effect on the RhoA/Rho kinase pathway [Morelli et al 2007] OAB or urgency-incontinence is at the level of the PAG or PMC and their connections, and possible treatments for this condition should target the micturition pathways at that level. '…”

Section: Phosphodiesterase (Pde) Inhibitorsmentioning

confidence: 99%

Prospective pharmacologic therapies for the overactive bladder

Andersson

2009

Therapeutic Advances in Urology

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Lower urinary tract symptoms (LUTS), overactive bladder syndrome (OAB) and detrusor overactivity (DO) are all conditions that can have major effects on quality of life and social functioning. Antimuscarinic drugs are first-line treatment-they often have good initial response rates, but adverse effects and decreasing efficacy cause long-term compliance problems, and alternatives are needed. The recognition of the functional contribution of the urothelium, the spontaneous myocyte activity during bladder filling, and the diversity of nerve transmitters has sparked interest in both peripheral and central modulation of LUTS/OAB/DO pathophysiology. There may be several new possibilities to treat LUTS/OAB/DO. 3 -AR agonists (YM178), PDE 5 inhibitors (sildenafil, tadalafil, vardenafil), vitamin D analogs (elocalcitol), combinations ( 1 -AR antagonist þ antimuscarinic), and drugs with a central mode of action (tramadol, aprepitant) all have Randomized controlled trial (RCT) documented efficacy. Which of these therapeutic principles will be developed to clinically useful treatments remains to be established.

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BXL‐628, a vitamin D receptor agonist effective in benign prostatic hyperplasia treatment, prevents RhoA activation and inhibits RhoA/Rho kinase signaling in rat and human bladder

Abstract: BXL-628 inhibits RhoA/Rho-kinase signaling, a calcium sensitizing pathway, suggesting its possible clinical use in the treatment of altered bladder contractility often associated with BPH-induced lower urinary tract symptoms.

Cited by 70 publications

References 45 publications

1,25-(OH)2D3 and its analogue BXL-628 inhibit high glucose-induced activation of RhoA/ROCK pathway in HK-2 cells

1,25-(OH)2D3 and its analogue BXL-628 inhibit high glucose-induced activation of RhoA/ROCK pathway in HK-2 cells

Treatment of Experimental Autoimmune Prostatitis in Nonobese Diabetic Mice by the Vitamin D Receptor Agonist Elocalcitol

Prospective pharmacologic therapies for the overactive bladder

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