AUA2023: BEST POSTERS Inhibition of Human Detrusor Smooth Muscle Cell Growth and Modulation of Cytoskeletal Organization by Immunomodulatory Imide Drugs
By: Alexander Tamalunas, Asst Prof, MD, University Hospital, LMU Munich, Germany; Amin Wendt, MS, University Hospital, LMU Munich, Germany; Florian Springer, MS, University Hospital, LMU Munich, Germany; Victor Vigodski, MS, University Hospital, LMU Munich, Germany; Anna Ciotkowska, MSc, University Hospital, LMU Munich, Germany; Beata Rutz, MSc, University Hospital, LMU Munich, Germany; Sheng Hu, MS, University Hospital, LMU Munich, Germany; Heiko Schulz, MD, University Hospital Munich, LMU Munich, Germany; Stephan Ledderose, MD, University Hospital Munich, LMU Munich, Germany; Elfriede Nößner, Prof, PhD, Immunoanalytics Research Group Tissue Control of Immunocytes, Helmholtz Center Munich, Germany; Christian G. Stief, Prof, MD, University Hospital, LMU Munich, Germany; Martin Hennenberg, Prof, PhD, University Hospital, LMU Munich, Germany | Posted on: 30 Aug 2023
Smooth muscle contraction is essential for lower urinary tract functions and occupies a central position in pathophysiology and treatment of lower urinary tract symptoms (LUTS), belonging to the most common nonmalignant diseases. LUTS include both voiding and storage symptoms.1,2 Urethral obstruction is most frequently caused as direct consequence of benign prostatic hyperplasia (BPH), leading to voiding symptoms by prostatic enlargement and increased smooth muscle tone in the hyperplastic prostate.3 Storage symptoms are caused by spontaneous contractions of the detrusor muscle, referred to as overactive bladder (OAB).4,5 A considerable proportion of patients with LUTS suggestive of BPH also suffer from OAB-related symptoms, subsumed in the term mixed LUTS.2 Targets for medical therapy in BPH and OAB are smooth muscle contraction in the prostate and bladder, and cellular growth in the prostate.3,6,7
While activation of α1-adrenoceptors causes smooth muscle contraction in the prostate stroma, hyperplastic prostate stromal and glandular growth is facilitated through dihydrotestosterone.3,8 Reduction of testosterone is catalyzed by 5α-reductase into its biologically more active metabolite dihydrotestosterone. As α1-adrenoceptor antagonists (α1-blockers) are used for immediate relief of LUTS by inhibiting adrenergic smooth muscle contraction, they are often administered in combination with 5α-reductase inhibitors for concomitant reduction of prostate size.7 However, current pharmacotherapy is characterized by obvious limitations: α1-adrenoceptor antagonists improve prostate symptom scores and urinary flow rates by no more than 50%, and 5α-reductase inhibitors reduce prostate size less than 30% after long-term use, contributing to high discontinuation rates and ultimately to the need for definitive surgery.9-12 As α1-adrenoceptor antagonists do not reduce prostate volume, combination therapies are a commonly applied option to reduce symptoms and to slow down disease progression.7,13-15
Spontaneous contractions of the detrusor smooth muscle (detrusor overactivity) are the primary cause of OAB and presumably of noncholinergic origin, while voiding contractions of the detrusor are caused by muscarinic receptors (M3 and M2 subtype).16,17 Consequently, smooth muscle tone of the detrusor is the target for pharmacological therapies of OAB-related storage symptoms.16,18 In the presence of LUTS secondary to BPH, detrusor overactivity may be a direct consequence of prostatic obstruction; aggravating symptoms and leading to mixed LUTS.19,20 Detrusor overactivity may also be the result of hypertrophy or thickening of the bladder wall.21,22 This can contribute to the symptoms of OAB, and mostly occurs because of mechanical stress in the bladder wall, or secondary to an obstructive prostate.21-24 Medical therapy for LUTS/OAB includes muscarinic receptor antagonists for relief of bladder contractions.2,4 During treatment of storage symptoms with antimuscarinics, the probability of becoming symptom-free ranges around 50% for incontinence and frequency, but is less for urgency (about 20%) and nocturia (about 10%).25 Thus, the more recent introduction of a β3-adrenoceptor agonist, mirabegron, for treatment of storage symptoms reflects the need for new substance classes for medical therapy of male LUTS.2,26
Recently, clinical trials have increasingly focused on combination therapies, acknowledging the high number of patients suffering from mixed LUTS.2,3 By combining α1-blockers with muscarinic receptor antagonists, smooth muscle contractions in the prostate and detrusor are both targeted at once. However, adverse events of either drug class are seen with combined treatment using α1-blockers and antimuscarinics, with the most common and bothersome side effects including ejaculation failure and therapy-limiting dry mouth.27 Thus, respective discontinuation rates of up to 90% due to treatment failure or therapy-limiting side effects highlight the limitations of current pharmacotherapy and the need for new therapeutic agents.28-30 In face of these limitations, together with the age-dependency of prevalence, demographic transition, and increasing case numbers, novel medications for LUTS are of high demand, which require (1) adequate understanding of prostate, bladder, and vascular smooth muscle contraction and (2) identification of putative novel candidate compounds.
Recent observations by our study group showed that immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide inhibited prostate smooth muscle contraction, and may exert regulative action of prostatic hyperplastic growth.31,32 In general, targets and compounds with impact on smooth muscle contraction of any smooth muscle-rich tissue, on actin organization, or myosin light chain phosphorylation are possible candidates, which merit consideration in the context of prostate and bladder smooth muscle contraction. In fact, actin organization and myosin light chain phosphorylation are essential prerequisites of smooth muscle contraction.8 However, the highest translational potential for new LUTS medication lies in drugs simultaneously inhibiting prostate and bladder smooth muscle contraction and cell proliferation, without the cardiovascular side effects of using a single compound.
Lenalidomide and pomalidomide are both structurally similar derivatives of thalidomide, known for causing birth defects following its use as an anti-emetic in pregnant women in the 1960s.33 Meanwhile, IMiDs are an orally available and highly established and effective treatment option in multiple myeloma.34 Thus, the translational value of thalidomide and its analogues is high—in particular, in elderly male patients, where the risk of teratogenicity does not apply.
Additionally, our study group could show that IMiDs inhibited α1-adrenergic, nonadrenergic and neurogenic prostate smooth muscle contractions, prostate stromal cell growth, and actin formation.31,32 However, data were previously limited to a line of prostate stromal cells, WPMY-1 cells, while data on human bladder detrusor smooth muscle cells (HBdSMC) were still lacking. The present study investigated the effects of IMiDs on proliferation, viability, toxicity, and actin organization of primary HBdSMC. Cytoskeletal organization was visualized by phalloidin staining, while cell growth was assessed using a 5-ethynyl-2-deoxyuridine and cell colony assay. Cell viability was quantified in CCK8 assay, and FACS. All 3 IMiDs significantly reduced the number of viable HBdSMC in a concentration- and time-dependent manner. Correspondingly, proliferation of HBdSMC was significantly reduced in a concentration-dependent manner, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization: while the cellular shape of control cells was characterized by many long and thin protrusions containing bundles of actin filaments; this structure collapsed after treatment with IMiDs.
To this day, the exact mechanisms of action of IMiDs remain mostly unclear, as they have the potential to work through many different pathways.35,36 At functional levels, we could recently show that IMiDs can inhibit human prostate and bladder smooth muscle contraction, while at the same time inhibiting prostate stromal and detrusor smooth muscle cell proliferation (ie, potentially inhibiting prostate growth and presumably bladder wall thickening). Thus, potently addressing 2 major mechanisms in LUTS. While current mono- and even combination therapies fail to adequately address voiding symptoms, there is now mounting evidence that thalidomide and its derivatives may be promising future treatment options in LUTS.2,8,31,37
Disclosures: No conflicts of interest exist.
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- Tamalunas A, Westhofen T, Schott M, et al. The impact of preoperative lower urinary tract symptoms medication on the functional performance of holmium laser enucleation of the prostate. Cent European J Urol. 2021;74(3):429-436.
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