Lung infections with multiresistant pathogens are a major problem among patients suffering from cystic fibrosis (CF). N-Chlorotaurine (NCT), a microbicidal active chlorine compound with no development of resistance, is well tolerated upon inhalation. The aim of this study was to investigate the in vitro bactericidal and fungicidal activity of NCT in artificial sputum medium (ASM), which mimics the composition of CF mucus. The medium was inoculated with bacteria (Staphylococcus aureus, including some methicillin-resistant S. aureus [MRSA] strains, Pseudomonas aeruginosa, and Escherichia coli) or spores of fungi (Aspergillus fumigatus, Aspergillus terreus, Candida albicans, Scedosporium apiospermum, Scedosporium boydii, Lomentospora prolificans, Scedosporium aurantiacum, Scedosporium minutisporum, Exophiala dermatitidis, and Geotrichum sp.), to final concentrations of 10 7 to 10 8 CFU/ml. NCT was added at 37°C, and time-kill assays were performed. At a concentration of 1% (10 mg/ml, 55 mM) NCT, bacteria and spores were killed within 10 min and 15 min, respectively, to the detection limit of 10 2 CFU/ml (reduction of 5 to 6 log 10 units). Reductions of 2 log 10 units were still achieved with 0.1% (bacteria) and 0.3% (fungi) NCT, largely within 10 to 30 min. Measurements by means of iodometric titration showed oxidizing activity for 1, 30, 60, and Ͼ60 min at concentrations of 0.1%, 0.3%, 0.5%, and 1.0% NCT, respectively, which matches the killing test results. NCT demonstrated broad-spectrum microbicidal activity in the milieu of CF mucus at concentrations ideal for clinical use. The microbicidal activity of NCT in ASM was even stronger than that in buffer solution; this was particularly pronounced for fungi. This finding can be explained largely by the formation, through transhalogenation, of monochloramine, which rapidly penetrates pathogens.

IL6/STAT3 signaling is associated with endocrine therapy resistance in prostate cancer, but therapies targeting this pathway in prostate cancer were unsuccessful in clinical trials so far. The mechanistic explanation for this phenomenon is currently unclear; however, IL6 has pleiotropic effects on a number of signaling pathways, including the androgen receptor (AR). Therefore, we investigated IL6-mediated AR activation in prostate cancer cell lines and ex vivo primary prostate tissue cultures in order to gain a better understanding on how to inhibit this process for future clinical trials. IL6 significantly increased androgendependent AR activity in LNCaP cells but importantly did not influence AR activity at castrate androgen levels. To identify the underlying mechanism, we investigated several signaling pathways but only found IL6-dependent changes in STAT3 signaling. Biochemical inhibition of STAT3 with the small-molecule inhibitor galiellalactone significantly reduced AR activity in several prostate and breast cancer cell lines. We confirmed the efficacy of galiellalactone in primary tissue slice cultures from radical prostatectomy samples. Galiellalactone significantly reduced the expression of the AR target genes PSA (P < 0.001), TMPRSS2 (P < 0.001), and FKBP5 (P ¼ 0.003) in benign tissue cultures (n ¼ 24). However, a high heterogeneity in the response of the malignant samples was discovered, and only a subset of tissue samples (4 out of 10) had decreased PSA expression upon galiellalactone treatment. Taken together, this finding demonstrates that targeting the IL6/STAT3 pathway with galiellalactone is a viable option to decrease AR activity in prostate tissue that may be applied in a personalized medicine approach. Mol Cancer Ther; 17(12); 2722-31. Ó2018 AACR.

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