Cynomorium songaricum Rupr demonstrates phytoestrogenic or phytoandrogenic like activities that attenuates benign prostatic hyperplasia via regulating steroid 5-α-reductase

Abstract

Ethnopharmacological relevance: Cynomorium songaricum Rupr. (CS) belongs to the genus of parasitic perennial flowering plants, mostly used in Chinese traditional medicine for benign prostatic hyperplasia (BPH) treatment. BPH is a chronic disease in men that both androgen and estrogen play a crucial role in promoting its development via their receptors. Previously we have showed that compounds from CS have the phytoestrogenic and/or phytoandrogenic activities that may have the potential suppressive effects on BPH, while the mechanism remains unclear.

Aim of the study: In this study, we aim to investigate the effect of CS and its derived compounds: luteolin (LUT), gallic acid (GA), protocatechuic acid (PA) and protocatechualdehyde (Pra) on inhibition of rat BPH and proliferation of BPH-1 cell line respectively, and further uncover whether it is related with the phytoestrogenic and / or phytoandrogenic activities.

Materials and methods: Estradiol/testosterone (1:100) was subcutaneous injected to induce BPH in a castrated rat model, and CS was orally administrated for 45 days. Then the weights of the body and prostate were recorded, the pathogenesis changes of prostate were analyzed by Hematoxylin and eosin (H&E) and immunohistochemical (IHC). The levels of 17β-estradiol (E₂), testosterone, and dihydrotestosterone (DHT) from rats' serum were measured by enzyme-linked immunosorbent assay (ELISA). In vitro, human benign prostatic epithelial cell BPH-1 was cultured and treated with or without different CS compounds and DHT or E₂. MTT and CCK-8 assays were performed to detect the regulatory effects on cell proliferation. The expressions of PCNA, AR, ERα, ERβ, and steroid 5-α-reductases (SRD5A1 and SRD5A2) were further analyzed by western blotting upon treatment.

Results: Treatment with CS significantly inhibited rat prostate enlargement, improved the pathological feature and reduced the thickness of smooth muscle layer. The up-regulated AR and ERα expressions and down-regulated ERβ in BPH rat prostate were significantly blocked after CS administration. Moreover, the enhanced values of E₂/testosterone and the level of DHT in serum were also strongly inhibited in CS group compared with those in BPH groups. In cellular level, LUT, GA, PA, or Pra significantly inhibited DHT- or E₂- induced BPH-1 cell proliferation and PCNA expressions. Consistently with the data in vivo, compounds from CS interfered the DHT or E₂-regulated AR, ERα and ERβ expressions in BPH-1 cells as well. Importantly, the dramatic increased SRD5A1 and SRD5A2 expressions were observed in BPH rat prostates and DHT or E₂-stimulated BPH-1 cells. However, treatment with CS in rat or with compounds isolated from CS in BPH-1 cells significantly blocked the induction of SRD5A1 and SRD5A2.

Conclusions: CS suppressed BPH development through interfering with prostatic AR, ERα/β, and SRD5A1/2 expressions, which provided evidence of CS for BPH treatment.

Keywords: Androgen receptor; Benign prostatic hyperplasia; Cynomorium songaricum Rupr.; Estrogen receptor α/β; Steroid 5-α-reductase ½.