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Abstract
WS® 1541 is a phytopharmaceutical drug combination containing a lipophilic extract from fruits of Sabal serrulata (WS® 1473) and an aqueous ethanolic extract from roots of Urtica dioica (WS® 1031). It is approved in several countries worldwide for the treatment of lower urinary tract syndrome (LUTS) linked to benign prostate hyperplasia (BPH). Clinical studies have demonstrated the efficacy of this unique combination in the treatment of BPH-related LUTS. However, its mechanisms of action in vivo remain partly uncharacterized. The aim of this study was to take advantage of a validated mouse model of BPH to better characterize its growth-inhibitory and anti-inflammatory properties. We used the probasin–prolactin (Pb-PRL) transgenic mouse model in which prostate-specific overexpression of PRL results in several features of the human disease including tissue hypertrophy, epithelial hyperplasia, increased stromal cellularity, inflammation, and LUTS. Six-month-old heterozygous Pb-PRL male mice were randomly distributed to five groups (11–12 animals/group) orally treated for 28 consecutive days with WS® 1541 (300, 600, or 900 mg/kg/day), the 5α-reductase inhibitor finasteride used as reference (5 mg/kg/day) or vehicle (olive oil 5 ml/kg/day). Administration of WS® 1541 was well tolerated and caused a dose-dependent reduction of prostate weight (vs. vehicle) that was statistically significant at the two highest doses. This effect was accompanied by a reduction in prostate cell proliferation as assessed by lower Ki-67 expression (qPCR and immunohistochemistry). In contrast, finasteride had no or only a mild effect on these parameters. The growth-inhibitory activity of WS® 1541 was accompanied by a strong anti-inflammatory effect as evidenced by the reduced infiltration of cells expressing the leukocyte common antigen CD45. In sharp contrast, finasteride significantly increased the prostate inflammatory status according to this readout. Molecular profiling (qPCR) of 23 selected pro-inflammatory genes confirmed the strong anti-inflammatory potency of WS® 1541 compared to finasteride. Since treatment of WS® 1541 did not interfere with transgene expression and activity in the prostate of Pb-PRL mice, the effects observed in this study are entirely attributable to the intrinsic pharmacological action of the drug combination.
Highlights
Benign prostate hyperplasia (BPH) is a common urological condition caused by the non-malignant enlargement of the prostate gland as men get older, and potentially leading to lower urinary tract symptoms (LUTS) and complications
These results confirmed the good tolerance of the oral-route treatments and established the administration of up to 900 mg/kg/day of WS R 1541 for consecutive 28 days as not toxic for experimental mice
Among the pro-inflammatory cytokines/chemokines and receptors that we investigated in this study, we identified IL-1β, IL-15, CCL2, CCL4, CCL7, CXCL1, CXCL6, CXCR4, and CCR7 as the preferential targets of WS R 1541 as all were downregulated in ≥2 lobes and/or at ≥2 doses (Figure 7)
Summary
Benign prostate hyperplasia (BPH) is a common urological condition caused by the non-malignant enlargement of the prostate gland as men get older, and potentially leading to lower urinary tract symptoms (LUTS) and complications. One-third of men older than 40 years will report bother related to LUTS (Speakman et al, 2015) and be proposed for a treatment. Medical treatment of LUTS intend to reduce cellular proliferation by inhibiting 5α-reductase enzymes involved in the conversion of testosterone into its active metabolite dihydrotestosterone (DHT), to decrease bladder overactivity, and/or to lower the prostatic smooth muscle tonus. Numerous drugs have become available, including α-blockers, 5α-reductase inhibitors (5ARIs), antimuscarinics, phosphodiesterase type 5 inhibitors (PDE5Is), and herbal medicinal products, used alone or in combination, and several others are under evaluation with the results of phase 2/3 studies still pending (Peyronnet et al, 2018). To date, all these drugs but 5ARIs have only demonstrated symptomatic effects, with no impact on the natural evolution of the disease (Oelke et al, 2013)
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