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

image
Figure. Effects of immunomodulatory imide drugs (IMiDs) in the lower urinary tract. While lower urinary tract symptoms (LUTS) consist of voiding (benign prostatic hyperplasia [BPH]) and storage disorders (overactive bladder [OAB]), new AUA and European Association of Urology guidelines consider the mounting number of patients suffering from both, so-called mixed LUTS. Recently, we could show that IMiDs (thalidomide, lenalidomide and pomalidomide) inhibit human prostate and bladder detrusor smooth muscle contraction, modulate cytoskeletal actin organization, and reduce prostate stromal and bladder detrusor smooth muscle cell growth at the same time, without showing cytotoxic effects. BPO indicates benign prostatic obstruction.

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.

  1. Oelke M, Kuczyk MA, Herrmann TR. [Pharmacological treatment of benign prostatic hyperplasia]. Urologe. 2009;48(11):1365-1377.
  2. Gravas S, Cornu JN, Gacci M, et al. Management of Non-neurogenic Male LUTS. EAU Guidelines edn presented at the EAU Annual Congress Milan 2021. ISBN 978-94-92671-13-4, 2021.
  3. Lepor H. Pathophysiology, epidemiology, and natural history of benign prostatic hyperplasia. Rev Urol. 2004;6( Suppl 9):S3-S10.
  4. Chapple C. Overview on the lower urinary tract. Handb Exp Pharmacol. 2011;(202):1-14.
  5. Patel AK, Chapple CR. Medical management of lower urinary tract symptoms in men: current treatment and future approaches. Nat Rev Urol. 2008;5(4):211-219.
  6. Nambiar AK, Bosch R, Cruz F, et al. EAU guidelines on assessment and nonsurgical management of urinary incontinence. Eur Urol. 2018;73(4):596-609.
  7. Oelke M, Bachmann A, Descazeaud A, et al. EAU guidelines on the treatment and follow-up of non-neurogenic male lower urinary tract symptoms including benign prostatic obstruction. Eur Urol. 2013;64(1):118-140.
  8. Hennenberg M, Stief CG, Gratzke C. Prostatic alpha1-adrenoceptors: new concepts of function, regulation, and intracellular signaling. Neurourol Urodyn. 2014;33(7):1074-1085.
  9. Magistro G, Stief CG. Surgery for benign prostatic obstruction. Lancet. 2020;396(10243):5-7.
  10. Michel MC, Mehlburger L, Bressel HU, Goepel M. Comparison of tamsulosin efficacy in subgroups of patients with lower urinary tract symptoms. Prostate Cancer Prostatic Dis. 1998;1(6):332-335.
  11. Naslund MJ, Miner M. A review of the clinical efficacy and safety of 5alpha-reductase inhibitors for the enlarged prostate. Clin Ther. 2007;29(1):17-25.
  12. 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.
  13. Roehrborn CG. Three months’ treatment with the alpha1-blocker alfuzosin does not affect total or transition zone volume of the prostate. Prostate Cancer Prostatic Dis. 2006;9(2):121-125.
  14. Roehrborn CG, Siami P, Barkin J, CombAT Study Group, et al. The effects of dutasteride, tamsulosin and combination therapy on lower urinary tract symptoms in men with benign prostatic hyperplasia and prostatic enlargement: 2-year results from the CombAT study. J Urol. 2008;179(2):616-621.
  15. Roehrborn CG, Siami P, Barkin J, et al. The effects of combination therapy with dutasteride and tamsulosin on clinical outcomes in men with symptomatic benign prostatic hyperplasia: 4-year results from the CombAT study. Eur Urol. 2010;57(1):123-131.
  16. Bschleipfer T, Wagenlehner F, Weidner W. [Etiology and pathogenesis of overactive bladder]. Urologe. 2011;50(4):477-480.
  17. Andersson KE. Detrusor contraction–focus on muscarinic receptors. Scand J Urol Nephrol Suppl. 2004;38(215):54-57.
  18. Andersson KE. Muscarinic acetylcholine receptors in the urinary tract. Handb Exp Pharmacol. 2011;(202):319-344.
  19. Hampel C, Gillitzer R, Pahernik S, Hohenfellner M, Thuroff JW. [Epidemiology and etiology of overactive bladder]. Urologe A. 2003;42(6):776-786.
  20. Schumacher S. [Epidemiology and etiology of urinary incontinence in the elderly]. Urologe. 2007;46(4):357-362.
  21. Andersson KE, Arner A. Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev. 2004;84(3):935-986.
  22. Oelke M. International Consultation on Incontinence-Research Society (ICI-RS) report on non-invasive urodynamics: the need of standardization of ultrasound bladder and detrusor wall thickness measurements to quantify bladder wall hypertrophy. Neurourol Urodyn. 2010;29(4):634-639.
  23. Yamaguchi O. Response of bladder smooth muscle cells to obstruction: signal transduction and the role of mechanosensors. Urology. 2004;63(3):11-16.
  24. Boopathi E, Gomes C, Zderic SA, et al. Mechanical stretch upregulates proteins involved in Ca2+ sensitization in urinary bladder smooth muscle hypertrophy. Am J Physiol Cell Physiol. 2014;307(6):C542-C553.
  25. Muderrisoglu AE, Oelke M, Schneider T, Murgas S, de la Rosette J, Michel MC. What are realistic expectations to become free of overactive bladder symptoms? Experience from non-interventional studies with propiverine. Adv Ther. 2022;39(6):2489-2501.
  26. Chapple C. Mirabegron: the first beta3-adrenoceptor agonist for overactive bladder (OAB): a summary of the phase III studies. BJU Int. 2014;113(6):847-848.
  27. Athanasopoulos A, Chapple C, Fowler C, et al. The role of antimuscarinics in the management of men with symptoms of overactive bladder associated with concomitant bladder outlet obstruction: an update. Eur Urol. 2011;60(1):94-105.
  28. Sexton CC, Notte SM, Maroulis C, et al. Persistence and adherence in the treatment of overactive bladder syndrome with anticholinergic therapy: a systematic review of the literature. Int J Clin Pract. 2011;65(5):567-585.
  29. Cindolo L, Pirozzi L, Fanizza C, et al. Drug adherence and clinical outcomes for patients Under pharmacological therapy for lower urinary tract symptoms related to benign prostatic hyperplasia: population-based cohort study. Eur Urol. 2015;68(3):418-425.
  30. Tamalunas A, Wendt A, Springer F, et al. Permixon®, hexane-extracted serenoa repens, inhibits human prostate and bladder smooth muscle contraction and exerts growth-related functions in human prostate stromal cells. Life Sci. 2022;308:120931.
  31. Tamalunas A, Sauckel C, Ciotkowska A, et al. Inhibition of human prostate stromal cell growth and smooth muscle contraction by thalidomide: a novel remedy in LUTS?. Prostate. 2021;81(7):377-389.
  32. Tamalunas A, Sauckel C, Ciotkowska A, et al. Lenalidomide and pomalidomide inhibit growth of prostate stromal cells and human prostate smooth muscle contraction. Life Sci. 2021;281:119771.
  33. Ito T, Ando H, Suzuki T, et al. Identification of a primary target of thalidomide teratogenicity. Science. 2010;327(5971):1345-1350.
  34. Cruz MP. Lenalidomide (revlimid): a thalidomide analogue in combination with dexamethasone For the treatment of all patients with multiple myeloma. P T. 2016;41(5):308-313.
  35. Leonard GD, Dahut WL, Gulley JL, Arlen PM, Figg WD. Docetaxel and thalidomide as a treatment option for androgen- independent, nonmetastatic prostate cancer. Rev Urol. 2003;5(Suppl 3):S65-S70.
  36. Eichner R, Heider M, Fernandez-Saiz V, et al. Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat Med. 2016;22(7):735-743.
  37. Fullhase C, Chapple C, Cornu JN, et al. Systematic review of combination drug therapy for non-neurogenic male lower urinary tract symptoms. Eur Urol. 2013;64(2):228-243.

advertisement

advertisement