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5?-reductase inhibitors impact prognosis of urothelial carcinoma.

ABSTRACT: BACKGROUND:5?-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5?-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, using the Taiwan National Health Insurance database. METHODS:The data of this retrospective cohort study were sourced from the Longitudinal Health Insurance Database of Taiwan, compiled by the Taiwan National Health Insurance database from 1996 to 2010. It consists of 18,530 men with bladder cancer, of whom 474 were 5-ARIs recipients and 4384 men with upper tract urothelial carcinoma, of whom 109 were 5-ARIs recipients. Propensity Score Matching on the age and geographic data was done at the ratio of 1:10. We analyzed the odds ratios (OR) and 95% confidence interval (CI) of the risk of bladder cancer death, bladder cancer recurrence rate and upper tract urothelial carcinoma related death by the 5-ARIs administration. RESULTS:Those who received 5-ARIs showed a lower risk of bladder cancer related death compared to nonusers in multivariable adjusted analysis (OR 0.835, 95% CI 0.71-0.98). However, there was no significant difference in the bladder cancer recurrence rate (OR 0.956, 95% CI 0.82-1.11) and upper tract urothelial carcinoma related mortality in multivariable adjusted analysis (OR 0.814, 95% CI 0.6-1.1). CONCLUSIONS:Patients who receive 5-ARIs have lower bladder cancer related mortality compared to those who don't. 5-ARIs may prove to be a viable strategy to improve bladder cancer outcomes.

SUBMITTER: Wang CS

PROVIDER: S-EPMC7488389 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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5α-reductase inhibitors impact prognosis of urothelial carcinoma.

Wang Chien-Sheng CS Li Ching-Chia CC Juan Yung-Shun YS Wu Wen-Jeng WJ Lee Hsiang-Ying HY

BMC cancer 20200911 1

<h4>Background</h4>5α-reductase inhibitors (5-ARIs) inhibit the pathway of converting the testosterone to dihydrotestosterone and are widely used in benign prostatic hyperplasia patients. Since androgen receptor activation may play a role in urothelial tumorigenesis, we conducted this retrospective cohort study to determine whether 5α-reductase inhibitors (5-ARIs) administration is associated with bladder cancer mortality, bladder cancer recurrence and upper tract urothelial carcinoma mortality, ...[more]

PMID: 32917158

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Project description:Objectives: To evaluate the ability of 18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to predict survivorship of patients with bladder cancer (BC) and/or upper urinary tract carcinoma (UUTC). Materials: Data from patients who underwent FDG PET/CT for suspicion of recurrent urothelial carcinoma (UC) between 2007 and 2015 were retrospectively collected in a multicenter study. Disease management after the introduction of FDG PET/CT in the diagnostic algorithm was assessed in all patients. Kaplan-Meier and log-rank analysis were computed for survival assessment. A Cox regression analysis was used to identify predictors of recurrence and death, for BC, UUTC, and concomitant BC and UUTC. Results: Data from 286 patients were collected. Of these, 212 had a history of BC, 38 of UUTC and 36 of concomitant BC and UUTC. Patient management was changed in 114/286 (40%) UC patients with the inclusion of FDG PET/CT, particularly in those with BC, reaching 74% (n = 90/122). After a mean follow-up period of 21 months (Interquartile range: 4-28 mo.), 136 patients (47.4%) had recurrence/progression of disease. Moreover, 131 subjects (45.6%) died. At Kaplan-Meier analyses, patients with BC and positive PET/CT had a worse overall survival than those with a negative scan (log-rank < 0.001). Furthermore, a negative PET/CT scan was associated with a lower recurrence rate than a positive examination, independently from the primary tumor site. At multivariate analysis, in patients with BC and UUTC, a positive FDG PET/CT resulted an independent predictor of disease-free and overall survival (p < 0,01). Conclusions: FDG PET/CT has the potential to change patient management, particularly for patients with BC. Furthermore, it can be considered a valid survival prediction tool after primary treatment in patients with recurrent UC. However, a firm recommendation cannot be made yet. Further prospective studies are necessary to confirm our findings.

Project description:Histone deacetylase inhibitors (HDACi) are promising anti-cancer drugs that could also be employed for urothelial carcinoma (UC) therapy. It is unclear, however, whether inhibition of all 11 zinc-dependent HDACs or of individual enzymes is more efficacious and specific. Here, we investigated the novel HDACi 19i (LMK235) with presumed preferential activity against class IIA HDAC4/5 in comparison to the pan-HDACi vorinostat (SAHA) and the HDAC4-specific HDACi TMP269 in UC cell lines with basal expression of HDAC4 and characterized two HDAC4-overexpressing UC cell lines.Cytotoxic concentrations 50% (CC50s) for HDACi were determined by MTT assay and high-content analysis-based fluorescent live/dead assay in UC cell lines with different expression of HDAC4 and as well as in normal urothelial cell cultures, HBLAK and HEK-293 cell lines. Effects of HDACis were analyzed by flow cytometry; molecular changes were followed by qRT-PCR and Western blots. UC lines overexpressing HDAC4 were established by lentiviral transduction. Inhibitor activity profiles of HDACi were obtained by current state in vitro assays, and docking analysis was performed using an updated crystal structure of HDAC4.In UC cell lines, 19i CC50s ranged around 1 ?M; control lines were similarly or less sensitive. Like SAHA, 19i increased the G2/M-fraction, disturbed mitosis, and elicited apoptosis or in some cells senescence. Thymidylate synthase expression was diminished, and p21CIP1 was induced; global histone acetylation and ?-tubulin acetylation also increased. In most cell lines, 19i as well as SAHA induced HDAC5 and HDAC4 mRNAs while rather repressing HDAC7. UC cell lines overexpressing HDAC4 were not significantly less sensitive to 19i. Reevaluation of the in vitro HDAC isoenzyme activity inhibition profile of 19i and its docking to HDAC4 using current assays suggested rather low activity against class IIA HDACs. The specific class IIA HDAC inhibitor TMP269 impeded proliferation of UC cell lines only at concentrations >?10 ?M.Anti-neoplastic effects of 19i on UC cells appear to be exerted by targeting class I HDACs. In fact, HDAC4 may rather impede UC growth. Our results suggest that targeting of class IIA HDACs 4/5 may not be optimal for UC therapy. Moreover, our investigation provides further evidence for cross-regulation of class IIA HDACs by class I HDACs.

Project description:BACKGROUND:Genomic profiling can be used to identify the predictive effect of genomic subsets for determining prognosis in bladder urothelial carcinoma (BUC) after radical cystectomy. This study aimed to investigate potential gene and pathway markers associated with prognosis in BUC. METHODS:A microarray dataset of BUC was obtained from The Cancer Genome Atlas database. Differentially expressed genes (DEGs) were identified by DESeq of the R platform. Kaplan-Meier analysis was applied for prognostic markers. Key pathways and genes were identified using bioinformatics tools, such as gene set enrichment analysis, gene ontology, the Kyoto Encyclopedia of Genes and Genomes, gene multiple association network integration algorithm (GeneMANIA), Search Tool for the Retrieval of Interacting Genes/Proteins, and Molecular Complex Detection. RESULTS:A comparative gene set enrichment analysis of tumor and adjacent normal tissues suggested BUC tumorigenesis resulted mainly from enrichment of cell cycle and DNA damage and repair-related biological processes and pathways, including TP53 and mitotic recombination. Two hundred and fifty-six genes were identified as potential prognosis-related DEGs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the potential prognosis-related DEGs were enriched in angiogenesis, including the cyclic adenosine monophosphate biosynthetic process, cyclic guanosine monophosphate-protein kinase G, mitogen-activated protein kinase, Rap1, and phosphoinositide-3-kinase-AKT signaling pathway. Nine hub genes, TAGLN, ACTA2, MYH11, CALD1, MYLK, GEM, PRELP, TPM2, and OGN, were identified from the intersection of protein-protein interaction and GeneMANIA networks. Module analysis of protein-protein interaction and GeneMANIA networks mainly showed enrichment of the cyclic guanosine monophosphate-protein kinase G signaling pathway, angiogenesis, cell proliferation, and differentiation, which are associated with tumor angiogenesis and cancer prognosis. CONCLUSION:Genes and pathways related to cell cycle and DNA damage and repair may play a crucial role in BUC pathogenesis, whereas those pertaining to tumor angiogenesis may be key factors in influencing BUC prognosis, especially in advanced disease stages.

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5?-reductase inhibitors impact prognosis of urothelial carcinoma.

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5α-reductase inhibitors impact prognosis of urothelial carcinoma.

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