15 research outputs found
Untersuchungen zu chemopräventiven Aktivitäten von Isoflavonoiden aus der Sojabohne (Glycine max) sowie deren im menschlichen Darm gebildeten reduktiven Metaboliten in humanen Prostatazellen
Das Prostatakarzinom ist die dritthäufigste maligne Erkrankung des Mannes weltweit, wobei viele asiatische Länder auffallend niedrige Inzidenzraten für diese Tumorform aufweisen. Möglicherweise vermindert der in Asien sehr hohe Verzehr von Sojaprodukte das Erkrankungsrisiko. Die Sojabohne enthält herausragend hohe Gehalte an Isoflavonoiden (IF). Die vorliegende Arbeit vergleicht die Wirkungen dieser Sojainhaltstoffe mit einigen aus ihnen im menschlichen Darm gebildeten Metaboliten an den humanen Prostatazelllinien LNCaP und LAPC-4 in vitro. Darüber hinaus erfolgten Untersuchungen mit dem Ziel, mögliche chemopräventive – also das Tumorrisiko senkende – Aktivitäten von Isoflavonoiden zu ermitteln. Das Soja-IF Genistein verminderte das Wachstum der Prostatazellen stärker als seine Metabolite. Die vom Soja-IF Daidzein abgeleiteten Metabolite besitzen z. T. ein höheres wachstumshemmendes Potential als ihre Vorstufe. Genistein schützt darüber hinaus vor oxidativ-induzierten DNA-Schäden und induziert einige Gene der zellulären antioxidativen Abwehr. Die vorliegende Arbeit liefert somit experimentelle Hinweise für chemopräventive Wirkungen von IF in Prostatazellen. Es erscheint daher möglich, dass ein häufiger Verzehr von Sojaprodukten über die so aufgenommenen Mengen an IF zu einer günstigen Beeinflussung des Prostatakarzinomrisikos führt und für einen Teil der im asiatischen Raum deutlich geringeren Inzidenz dieser Erkrankung verantwortlich ist
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Genistein protects prostate cells against hydrogen peroxide-induced DNA damage and induces expression of genes involved in the defence against oxidative stress
Prostate cancer is one of the most frequent cancer types in Western societies and predominately occurs in the elderly male. The strong age-related increase of prostate cancer is associated with a progressive accumulation of oxidative DNA damage which is presumably supported by a decline of the cellular antioxidative defence during ageing. Risk of developing prostate cancer is much lower in many Asian countries where soy food is an integral part of diet. Therefore, isoflavones from soy were suggested to have chemopreventive activities in prostate cells. Here, we have investigated the hypothesis that the soy-isoflavone genistein could protect DNA of LAPC-4 prostate cells from oxidative stress-related damage by enhancing the expression of antioxidative genes and proteins. A 24 h preincubation with genistein (1-30 microM) protected cells from hydrogen peroxide-induced DNA damage, as determined by the comet assay. Analysis of two cDNA macroarrays, each containing 96 genes of biotransformation and stress response, revealed a modulated expression of 3 genes at 1 microM and of 19 genes at 10 microM genistein. Real-time PCR confirmed the induction of three genes encoding products with antioxidant activities, namely glutathione reductase (2.7-fold), microsomal glutathione S-transferase 1 (1.9-fold) and metallothionein 1X (6.3-fold), at 1-30 microM genistein. 17Beta-estradiol, in contrast, decreased the expression of metallothionein 1X at 0.3 microM (2.0-fold), possibly pointing to an estrogen receptor-mediated regulation of this gene. Immunocytochemical staining revealed an induction of metallothionein proteins at 30 microM genistein, while their intracellular localization was unaffected. Metallothioneins were previously found to protect cells from hydrogen peroxide-induced DNA damage. Hence, our findings indicate that genistein protects prostate cells from oxidative stress-related DNA damage presumably by inducing the expression of antioxidative products, such as metallothioneins. Genistein, therefore, might counteract the age-related decline of important antioxidative defence systems which in turn maintain DNA integrity
The role of residual gadolinium in the induction of nephrogenic systemic fibrosis-like skin lesions in rats
Simultaneous evaluation of anti-EGFR-induced tumour and adverse skin effects in a microfluidic human 3D co-culture model
Abstract Antibody therapies targeting the epithelial growth factor receptor (EGFR) are being increasingly applied in cancer therapy. However, increased tumour containment correlates proportionally with the severity of well-known adverse events in skin. The prediction of the latter is not currently possible in conventional in vitro systems and limited in existing laboratory animal models. Here we established a repeated dose “safficacy” test assay for the simultaneous generation of safety and efficacy data. Therefore, a commercially available multi-organ chip platform connecting two organ culture compartments was adapted for the microfluidic co-culture of human H292 lung cancer microtissues and human full-thickness skin equivalents. Repeated dose treatment of the anti-EGFR-antibody cetuximab showed an increased pro-apoptotic related gene expression in the tumour microtissues. Simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated, demonstrating crucial inhibitory effects on the physiological skin cell turnover. Furthermore, antibody exposure modulated the release of CXCL8 and CXCL10, reflecting the pattern changes seen in antibody-treated patients. The combination of a metastatic tumour environment with a miniaturized healthy organotypic human skin equivalent make this “safficacy” assay an ideal tool for evaluation of the therapeutic index of EGFR inhibitors and other promising oncology candidates
The enhanced value of combining conventional and "omics" analyses in early assessment of drug-induced hepatobiliary injury
The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling (" omics" ) technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyzed in relation to routine clinical chemistry and histopathology. Four of the sixteen hepato- and/or nephrotoxicants given to rats for 1, 3, or 14. days at two dose levels induced similar histopathological effects. These were characterized by bile duct necrosis and hyperplasia and/or increased bilirubin and cholestasis, in addition to hepatocyte necrosis and regeneration, hepatocyte hypertrophy, and hepatic inflammation. Combined analysis of liver transcriptomics data from these studies revealed common gene expression changes which allowed the development of a potential sequence of events on a mechanistic level in accordance with classical endpoint observations. This included genes implicated in early stress responses, regenerative processes, inflammation with inflammatory cell immigration, fibrotic processes, and cholestasis encompassing deregulation of certain membrane transporters. Furthermore, a preliminary classification analysis using transcriptomics data suggested that prediction of cholestasis may be possible based on gene expression changes seen at earlier time-points. Targeted bile acid analysis, based on LC-MS metabonomics data demonstrating increased levels of conjugated or unconjugated bile acids in response to individual compounds, did not provide earlier detection of toxicity as compared to conventional parameters, but may allow distinction of different types of hepatobiliary toxicity. Overall, liver transcriptomics data delivered mechanistic and molecular details in addition to the classical endpoint observations which were further enhanced by targeted bile acid analysis using LC/MS metabonomics. © 2010 Elsevier Inc
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Equol: a comparison of the effects of the racemic compound with that of the purified S-enantiomer on the growth, invasion, and DNA integrity of breast and prostate cells in vitro
It has been postulated that the R- and S-equol enantiomers have different biological properties given their different binding affinities for the estrogen receptor. S-(-)equol is produced via the bacterial conversion of the soy isoflavone daidzein in the gut. We have compared the biological effects of purified S-equol to that of racemic (R and S) equol on breast and prostate cancer cells of varying receptor status in vitro. Both racemic and S-equol inhibited the growth of the breast cancer cell line MDA-MB-231 (> or = 10 microM) and the prostate cancer cell lines LNCaP (> or = 5 microM) and LAPC-4 (> or = 2.5 microM). The compounds also showed equipotent effects in inhibiting the invasion of MDA-MB-231 and PC-3 cancer cells through matrigel. S-equol (1, 10, 30 microM) was unable to prevent DNA damage in MCF-7 or MCF-10A breast cells following exposure to 2-hydroxy-4-nonenal, menadione, or benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide. In contrast, racemic equol (10, 30 microM) prevented DNA damage in MCF-10A cells following exposure to 2-hydroxy-4-nonenal or menadione. These findings suggest that racemic equol has strong antigenotoxic activity in contrast to the purified S-equol enantiomer implicating the R-, rather than the S-enantiomer as being responsible for the antioxidant effects of equol, a finding that may have implications for the in vivo chemoprotective properties of equol
Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase
Inhibition of monopolar spindle 1 MPS1 kinase represents a novel approach to cancer treatment instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series triazolopyridines and imidazopyrazines . The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10 fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy model
Nano-antennae assisted emission of extreme ultraviolet radiation
Pfullmann N, Noack M, de Andrade JC, et al. Nano-antennae assisted emission of extreme ultraviolet radiation. Annalen der Physik. 2014;526(3-4):119-134.High-order harmonic generation in xenon with oscillator repetition rates is studied. The necessary intensity is reached via plasmonic field enhancement at nanostructured arrays of bow-tie gold antennae. The theoretical analysis focuses on the thermal properties and the damage threshold of the bow-tie antennae. On the experimental side the number of contributing atoms is determined and optimized. Extreme ultraviolet radiation is successfully observed with photon fluxes almost an order of magnitude larger than previously reported. High-order harmonic generation in xenon with oscillator repetition rates is studied. The necessary intensity is reached via plasmonic field enhancement at nanostructured arrays of bow-tie gold antennae. The theoretical analysis focuses on the thermal properties and the damage threshold of the bow-tie antennae. On the experimental side the number of contributing atoms is determined and optimized. image</graphi