Inhibition of human prostate stromal cell growth and smooth muscle contraction by thalidomide: A novel remedy in LUTS?

Abstract

Background Medical treatment in benign prostatic hyperplasia targets prostate size to prevent disease progression, complications, and surgery, and prostate smooth muscle tone for rapid relief of lower urinary tract symptoms. Combination therapies are still required to target both at once. However, current medications are insufficient, due to an unfavorable balance between side effects and efficacy. The limited efficacy of α1‐blockers may be due to nonadrenergic mediators like endothelin‐1 and thromboxane A2 (TXA2), which keep up prostate smooth muscle contraction even in the presence of α1‐blockers. Consequently, future options with higher efficacy need to target α1‐adrenergic and nonadrenergic contractions as well as stromal cell growth at once. Thalidomide has been approved as an oral medication for various diseases, including the treatment of prostate cancer. Therefore, we investigated the effect of thalidomide on cellular functions of prostate stromal cells and human prostate smooth muscle contraction. Methods Cytoskeletal organization was visualized by phalloidin staining, cell growth was assessed by 5‐ethynyl‐2ʹ‐deoxyuridine assay, cell viability by cell counting kit‐8, and apoptosis and cell death by flow cytometry in cultured prostate stromal cells (WPMY‐1). Contractions of human prostate tissues from radical prostatectomy were studied in an organ bath, where they were induced by the α1‐adrenoceptor agonists methoxamine, noradrenaline, phenylephrine, and the nonadrenergic agonists endothelin‐1, TXA2 analog U46619, or electric field stimulation (EFS). Results Thalidomide significantly reduced the proliferation of WPMY‐1 cells, which was time‐ and concentration‐dependent (10–300 µM). In parallel, organization of actin filaments collapsed after treatment with thalidomide. Thalidomide (30–100 µM) inhibited noradrenaline‐, phenylephrine‐, and methoxamine‐induced contractions, as well as nonadrenergic contractions induced by endothelin‐1 and U46619, and neurogenic contractions induced by EFS. No reduction in viability and no increases in apoptosis or in cell death were observed in WPMY‐1 cells. Conclusions Thalidomide impairs the growth of human prostate stromal cells, without showing a decrease in cell viability. In parallel, thalidomide inhibits adrenergic, neurogenic, and nonadrenergic contractions. This may be explained by a breakdown of the actin cytoskeleton. In vivo, urodynamic effects of thalidomide appear possible and may even exceed those of α1‐blockers or combination therapies.

The efficiency of amygdalin and doxorubicin combination on hepatocellular carcinoma and stromal myofibroblastic prostatic cells

“…These data coincide well and could be explained by the downregulation of BAX by the same treatment groups and explains the lack of cytotoxic effect of the three treatment regimens on WPMY-1 cells in the present MTT assay. Recently, similar results were obtained by Tamalunas et al, (2021), who studied how Thalidomide affected the biological functions of normal WPMY-1 stromal cells and the contraction of human smooth muscles. WPMY-1 cell growth was moderately affected by Thalidomide.…”

Alteration of the Expression and Functional Activities of Myosin II Isoforms in Enlarged Hyperplastic Prostates

“…In fact, a study has revealed that proliferation markers (PCNA and Ki67) could only be detected in glandular contents. Thus, the proliferation of mesenchymal cells can be assumed to originate from an epithelial-mesenchymal transition modulated by TGF-β [37,38]. SM plays a crucial role in the pathophysiology of BPH/LUTS despite the deterioration of the contractile apparatus and force generation in the enlarged prostate.…”

Glutathione Peroxidase 3 induced mitochondria-mediated apoptosis via AMPK /ERK1/2 pathway and resisted autophagy-related ferroptosis via AMPK/mTOR pathway in hyperplastic prostate

“…Lower urinary tract symptoms (LUTS), often secondary to BPH, are worrisome complication that place significant encumbrance on patients’ quality of life [ 2 ]. The increase in the number of periurethral epithelial and stromal cells characterizes BPH histopathologically due to the maladjustment of cell proliferation and death [ 3 ]. Although the molecular mechanism of BPH have been extensively studied, including a disequilibrium of sex hormone [ 4 ], stromal-epithelial interactions [ 5 ], cytokins [ 6 ], autoimmune [ 7 ] and oxidative stress (OS) [ 8 ], the exact pathogenesis remains unclear.…”