Lysophosphatidic acid stimulates proliferation of cultured smooth muscle cells from human BPH tissue: Sildenafil and papaverin generate inhibition

• Published in: The Prostate 2002-04, Vol.51 (1), p.50-58
• Main Authors: Adolfsson, Per I., Ahlstrand, Christer, Varenhorst, Eberhard, Svensson, Samuel P.S.
• Format: Article
• Language: English
• Subjects: [35S]-methionine; [3H]-thymidine; [H-3]-thymidine; [S-35]-methionine; Biological and medical sciences; BPH; cAMP; Cell Division - drug effects; Cells, Cultured; cGMP; Colforsin - pharmacology; Cyclic AMP - metabolism; Cyclic AMP - physiology; Cyclic GMP - metabolism; Cyclic GMP - physiology; DNA - analysis; DNA - biosynthesis; Dose-Response Relationship, Drug; Growth Inhibitors - pharmacology; Humans; hyperplastic; Lysophospholipids - antagonists & inhibitors; Lysophospholipids - pharmacology; Lysophospholipids - physiology; Male; Medical sciences; MEDICIN; MEDICINE; Muscle, Smooth - drug effects; Muscle, Smooth - pathology; Nephrology. Urinary tract diseases; Papaverine - pharmacology; PDE; Phosphodiesterase Inhibitors - pharmacology; Piperazines - pharmacology; proliferation; Prostatic Hyperplasia - pathology; Protein Biosynthesis; Proteins - analysis; Purines; Purinones - pharmacology; Sildenafil Citrate; SMC; Stimulation, Chemical; Sulfones; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0270-4137; 1097-0045; 1097-0045
• DOI: 10.1002/pros.10077

Background The endogenous substance lysophosphatidic acid (LPA) has been found to generate proliferation of cultured smooth muscle cells (SMC). Therefore, the effect of LPA on human benign prostate hyperplasia (BPH) could be of interest. Methods The proliferative effect of LPA on cultured human prostatic SMC from specimens obtained at trans‐urethral resection of the prostate (TURP) because of BPH, was analyzed by [3H]‐thymidine and [35S]‐methionine incorporation. In addition, LPA stimulated BPH SMC were treated with papaverin, forskolin, sildenafil or zaprinast, well known to increase the intracellular level of cAMP or cGMP. Results LPA produced a dose‐dependent increase in BPH SMC, both regarding DNA‐ and protein‐synthesis with EC50 values of 3 and 10 μM, respectively. Furthermore, both papaverin, a general phosphodiesterase inhibitor regarding cAMP hydrolyzes, and forskolin, an adenylyl cyclase stimulating agent, inhibited the LPA‐stimulated DNA replication in a dose dependent manner with IC50 = 2.5, and 0.35 μM, respectively. cGMP increasing agents, such as the NO‐donors SIN‐1 and SNAP, produced a weak anti‐proliferative response. However, both phosphodiesterase 5 inhibitors sildenafil (Viagra®) and zaprinast efficiently blocked DNA replication. In addition, when the protein synthesis was examined, we found that the LPA response was significantly inhibited by forskolin and papaverin. Conclusions The major conclusion of this investigation is that the endogenous serum component LPA, is able to promote human BPH SMC growth. In addition, our study indicates that cyclic nucleotides can inhibit this effect. Future clinical studies will be needed to determine if different specific phosphodiesterase inhibitors per se or in combination could represent a new therapeutic possibility for the treatment of BPH. Prostate 51:50–58, 2002. © 2002 Wiley‐Liss, Inc.