Catherine A. Thomas

Investigations into the presence of functional ß1, ß2 and ß3-adrenoceptors in urothelium and detrusor of human bladder

Purpose: We investigated the presence of functional s1, s2 and s3-adrenoceptor in urothelium and detrusor muscle of human bladder through in vitro pharmacology of selective s3 adrenoceptor agonist solabegron. Materials and Methods: Expression of these adrenoceptors in surgically separated human urothelium and detrusor muscle were investigated using RT-PCR. The effects of activating these receptors were studied by determining the relaxation produced by s-adrenoceptors agonist in pre-contracted human detrusor strips. Results: The results confirmed the presence of mRNA for s1, s2 and s3-adrenoceptor in both human urothelium and detrusor. In an in vitro functional bladder assay, Solabegron and other agonists for s-adrenoceptors such as procaterol and isoproterenol evoked potent concentration-dependent relaxation of isolated human bladder strips with pD2 values of 8.73 ± 0.19, 5.08 ± 0.48 and 6.28 ± 0.54, respectively. Conclusions: Selective s3-adrenoceptor agonist may be a potential new treatment for the overactive bladder OAB syndrome. Existence of s3-adrenoceptor mRNA exists in the urothelium in addition to the detrusor muscle suggest multiple site of actions for the s3-adrenoceptor in the lower urinary tract.

Botulinum-A toxin: an exciting new treatment option for prostatic disease

Recently, botulinum neurotoxin type A (BoNT‐A) application in the lower urinary tract has been extended to prostate disorders and we would like to review the literature on the mechanisms of action and clinical efficacy of BoNT‐A treatment in the prostate. The information was gathered from MEDLINE, abstracts from recent urological meetings and from personal experience. BoNT has demonstrated promising preliminary results for male prostatic disease and translational research suggests a novel mechanism of action of BoNT in the prostate. It is important to remember that the application of BoNT in the prostate is not approved by the regulatory agencies and caution should be applied until larger randomised clinical studies are completed.

Botulinum: A toxin for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms

Botulinum neurotoxin (BoNT) has been called the most poisonous poison and a potential bioterrorism weapon, and yet modern medicine has been able to harvest the elegant and specific activity of this toxin to treat a variety of medical conditions. BoNT application recently has been extended to prostate disorders, and this article reviews the literature on the mechanisms of action and clinical efficacy of BoNT treatment in the prostate. BoNT has demonstrated promising preliminary results for male lower urinary tract symptoms, and translational research suggests novel mechanism of action of BoNT in the prostate. It is important to remember that the application of BoNT in the prostate is not approved by the regulatory agencies and caution should be applied until larger randomized clinical studies are completed.

Tubulin-Perturbing Naphthoquinone Spiroketals

Several natural and synthetic naphthoquinone spiroketals are potent inhibitors of the thioredoxin–thioredoxin reductase redox system. Based on the antimitotic and weak antitubulin actions noted for SR‐7 ([8‐(furan‐3‐ylmethoxy)‐1‐oxo‐1,4‐dihydronaphthalene‐4‐spiro‐2′‐naphtho[1″,8″‐de][1′,3′][dioxin]), a library of related compounds was screened for tubulin‐perturbing properties. Two compounds, TH‐169 (5′‐hydroxy‐4′H‐spiro[1,3‐dioxolane‐2,1′‐naphthalen]‐4′‐one) and TH‐223 (5′‐methoxy‐4′H‐spiro[1,3‐dioxane‐2,1′‐naphthalen]‐4′‐one), had substantial effects on tubulin assembly and were antiproliferative at low micromolar concentrations. TH‐169 was the most potent at blocking GTP‐dependent polymerization of 10 μm tubulin in vitro with a remarkable 50% inhibitory concentration of ca. 400 nm. It had no effect on paclitaxel‐induced microtubule assembly and did not cause microtubule hypernucleation. TH‐169 failed to compete with colchicine for binding to β‐tubulin. The 50% antiproliferative concentration of TH‐169 against human cancer cells was at or slightly below 1 μm. Flow cytometry showed that 1 μm TH‐169 caused an increase in G2/M and hypodiploid cells. TH‐169 eliminated the PC‐3 cells’ polyploid population and increased their expression of p21WAF1 and Hsp70 in a concentration‐dependent manner. The antiproliferative effect of TH‐169 was irreversible and independent of changes in caspases, actin, tubulin, glyceraldehyde phosphate dehydrogenase or Bcl‐xS/L. This structurally simple naphthoquinone spiroketal represents a small molecule, tubulin‐interactive agent with a novel apoptotic pathway and attractive biological function.

(Z)-1,1-Dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane induces concentration-dependent growth inhibition, apoptosis, and coordinates regulation of apoptotic genes in TRAMP cells

(Z)-1-1-Dichloro-2,3-diphenylcyclopropane (A(II)) and (Z)-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane [2-(4-methoxyphenyl)-A(II)] inhibit tubulin polymerization, PSA production, and the proliferation of human prostate cancer cells. The actions of the agents were studied in three transgenic adenocarcinomas of the mouse prostate (TRAMP) cell lines. Antiproliferative potencies were determined and cells treated with the more potent 2-(4-methoxyphenyl)-A(II) were examined for induction of apoptosis. Microarray analyses were conducted to determine the apoptosis-related genes up- and down-regulated by the agent. 2-(4-Methoxyphenyl)-A(II) concentration-dependently inhibited growth of all three cell lines. Fifty percent and 100% growth inhibitory and 50% lethal concentrations were determined to be 0.3, 1.5, and 5 muM, respectively. Minimum detectable apoptosis-inducing concentrations by ELISA were 0.10 to 0.14 muM. PARP cleavage and two-color flow cytometry assays verified apoptosis induction. Microarray analyses showed Bok and Siva-pending to be up-regulated and that Birc, Dad1, and Atf5 were down-regulated. 2-(4-methoxyphenyl)-A(II) inhibits proliferation and induces apoptosis in the in vivo-adaptable TRAMP cells, suggesting the compound should be further examined in preclinical models.