Stefan Wölfl
Heidelberg University
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Featured researches published by Stefan Wölfl.
Journal of Medicinal Chemistry | 2010
Riccardo Rubbiani; Igor Kitanovic; Hamed Alborzinia; Suzan Can; Ana Kitanovic; Liliane A. Onambele; Maria Stefanopoulou; Yvonne Geldmacher; William S. Sheldrick; Gerhard Wolber; Aram Prokop; Stefan Wölfl; Ingo Ott
Gold(I) complexes such as auranofin have been used for decades to treat symptoms of rheumatoid arthritis and have also demonstrated a considerable potential as new anticancer drugs. The enzyme thioredoxin reductase (TrxR) is considered as the most relevant molecular target for these species. The here investigated gold(I) complexes with benzimidazole derived N-heterocyclic carbene (NHC) ligands represent a promising class of gold coordination compounds with a good stability against the thiol glutathione. TrxR was selectively inhibited by in comparison to the closely related enzyme glutathione reductase, and all complexes triggered significant antiproliferative effects in cultured tumor cells. More detailed studies on a selected complex revealed a distinct pharmacodynamic profile including the high increase of reactive oxygen species formation, apoptosis induction, strong effects on cellular metabolism (related to cell surface properties, respiration, and glycolysis), inhibition of mitochondrial respiration and activity against resistant cell lines.
ChemMedChem | 2008
Ulrich Schatzschneider; Johanna Niesel; Ingo Ott; Ronald Gust; Hamed Alborzinia; Stefan Wölfl
A series of five ruthenium(II) polypyridyl complexes [Ru(bpy)2(NN)]Cl2 was tested against human HT‐29 and MCF‐7 cancer cell lines. Cellular uptake efficiency and cytotoxicity were found to increase with the size of the aromatic surface area of the NN ligand. The most active compound carrying the dppn ligand exhibits a low micromolar IC50 value against both cell lines comparable to that of cisplatin under similar conditions. Continuous measurement of oxygen consumption, extracellular acidification rate, and impedance of the cell layer with a chip‐based sensor system upon exposure to the complexes showed only small changes for the first two parameters throughout the series. A significant and irreversible decrease in impedance was, however, found for the dppn compound. This suggests that its biological activity is related to modifications in cell morphology or cell–cell and cell–matrix contacts.
Journal of Medicinal Chemistry | 2011
Riccardo Rubbiani; Suzan Can; Igor Kitanovic; Hamed Alborzinia; Maria Stefanopoulou; Malte Kokoschka; Susann Mönchgesang; William S. Sheldrick; Stefan Wölfl; Ingo Ott
Gold(I) complexes with a 1,3-diethylbenzimidazol-2-ylidene N-heterocyclic carbene (NHC) ligand of the type NHC-Au-L (L=-Cl, -NHC, or -PPh3) were comparatively evaluated as thioredoxin reductase (TrxR) inhibitors and antimitochondrial anticancer agents. Different effects were noted in various biochemical assays (e.g., inhibition of TrxR, cellular and mitochondrial uptake, or effects on mitochondrial membrane potential), and this was related to properties of the complexes such as bond dissociation energies and overall charge. Remarkable antiproliferative effects, a strong induction of apoptosis, and enhancement of reactive oxygen species (ROS) formation as well as other effects on tumor cell metabolism confirmed the promising potential of the complexes as novel anticancer chemotherapeutics.
Molecular and Cellular Biology | 1999
Martin C. Schmidt; Rhonda R. McCartney; Xudong Zhang; Tommy S. Tillman; Harry Solimeo; Stefan Wölfl; Ciprian Almonte; Simon C. Watkins
ABSTRACT The Std1 protein modulates the expression of glucose-regulated genes, but its exact molecular role in this process is unclear. A two-hybrid screen for Std1-interacting proteins identified the hydrophilic C-terminal domains of the glucose sensors, Snf3 and Rgt2. The homologue of Std1, Mth1, behaves differently from Std1 in this assay by interacting with Snf3 but not Rgt2. Genetic interactions between STD1, MTH1, SNF3, andRGT2 suggest that the glucose signaling is mediated, at least in part, through interactions of the products of these four genes. Mutations in MTH1 can suppress the raffinose growth defect of a snf3 mutant as well as the glucose fermentation defect present in cells lacking both glucose sensors (snf3 rgt2). Genetic suppression by mutations in MTH1 is likely to be due to the increased and unregulated expression of hexose transporter genes. In media lacking glucose or with low levels of glucose, the hexose transporter genes are subject to repression by a mechanism that requires the Std1 and Mth1 proteins. An additional mechanism for glucose sensing must exist since a strain lacking all four genes (snf3 rgt2 std1 mth1) is still able to regulateSUC2 gene expression in response to changes in glucose concentration. Finally, studies with green fluorescent protein fusions indicate that Std1 is localized to the cell periphery and the cell nucleus, supporting the idea that it may transduce signals from the plasma membrane to the nucleus.
The Journal of Neuroscience | 2009
Wannan Tang; Ingrid Ehrlich; Steffen B. E. Wolff; Ann-Marie Michalski; Stefan Wölfl; Mazahir T. Hasan; Andreas Lüthi; Rolf Sprengel
A method allowing for efficient and quantitative coexpression of multiple heterologous proteins in neurons in vivo would be highly valuable for many applications in neuroscience. To date, different approaches, such as internal ribosomal entry site (IRES) elements ([Douin et al., 2004][1]),
The Journal of Neuroscience | 2008
M. A. Willaredt; Kerstin Hasenpusch-Theil; H. A. R. Gardner; I. Kitanovic; Vera Catherine Hirschfeld-Warneken; C. P. Gojak; K. Gorgas; C. L. Bradford; Joachim P. Spatz; Stefan Wölfl; Thomas Theil; Kerry Lee Tucker
Primary cilia are important sites of signal transduction involved in a wide range of developmental and postnatal functions. Proteolytic processing of the transcription factor Gli3, for example, occurs in primary cilia, and defects in intraflagellar transport (IFT), which is crucial for the maintenance of primary cilia, can lead to severe developmental defects and diseases. Here we report an essential role of primary cilia in forebrain development. Uncovered by N-ethyl-N-nitrosourea-mutagenesis, cobblestone is a hypomorphic allele of the IFT gene Ift88, in which Ift88 mRNA and protein levels are reduced by 70–80%. cobblestone mutants are distinguished by subpial heterotopias in the forebrain. Mutants show both severe defects in the formation of dorsomedial telencephalic structures, such as the choroid plexus, cortical hem and hippocampus, and also a relaxation of both dorsal-ventral and rostral-caudal compartmental boundaries. These defects phenocopy many of the abnormalities seen in the Gli3 mutant forebrain, and we show that Gli3 proteolytic processing is reduced, leading to an accumulation of the full-length activator isoform. In addition, we observe an upregulation of canonical Wnt signaling in the neocortex and in the caudal forebrain. Interestingly, the ultrastructure and morphology of ventricular cilia in the cobblestone mutants remains intact. Together, these results indicate a critical role for ciliary function in the developing forebrain.
Angewandte Chemie | 2012
Andreas Uwe Meyer; Christoph P. Bagowski; Malte Kokoschka; Maria Stefanopoulou; Hamed Alborzinia; Suzan Can; Danielle H. Vlecken; William S. Sheldrick; Stefan Wölfl; Ingo Ott
Gold complexes have a long tradition in the treatment of the symptoms of rheumatoid arthritis. 2] Therapeutically used drugs include mainly gold(I) thiolates (e.g. aurothiomalate and auranofin), which belong to the group of diseasemodifying antirheumatic drugs (DMARDs) that are used to slow down or stop the progression of this severe and disabling rheumatic disorder. Interestingly, in vitro studies on cultured tumor cells have also indicated the considerable potential of this class of metallodrugs for tumor chemotherapy, and thioredoxin reductase is one of the enzymes identified as a critical target. Intensified research on the development of gold antitumor drugs has led to many active species such as gold(I) complexes with phosphine, thiolate, chloride, and carbene ligands as well as gold(III) derivatives. 10–12] However, a major issue in the development of new bioactive gold complexes is the preparation of complexes that show suitable stability under physiological conditions. Gold complexes with alkynyl ligands, which are widely used because of their catalytic and luminescent properties, might display reasonably stable coordinative bonds. In fact, recent initial reports on the bioactivity of alkynyl gold complexes indicate that this type of organometallic complex offers opportunities for the development of new chemotherapeutics against cancer and infectious diseases. Despite these prospectives, only three studies on the biological potential of alkynyl gold complexes have been reported so far. Here, we present the outcome of a pilot study aimed at establishing the biological profile of alkynyl phosphine gold(I) complexes. Our study shows that the critical target enzyme thioredoxin reductase can be efficiently and selectively inhibited and that cysteine and selenocysteine residues are presumably the sites of molecular interaction with the enzyme. Moreover, we quantified the cellular uptake of the complexes, established their effects on tumor cell metabolism and mitochondrial respiration, and investigated their antiangiogenic properties in zebrafish embryos. A series of six alkynyl gold(I) complexes (1–6, see Figure 1) was prepared by reacting the respective alkynes with chloro(triphenylphosphine)gold(I). The structures were confirmed by H, C, P NMR, and IR spectroscopy and
Mutation Research-genetic Toxicology and Environmental Mutagenesis | 2000
Victor Afanassiev; Mark Sefton; Thaddao Anantachaiyong; Gordon Barker; Richard M. Walmsley; Stefan Wölfl
Yeast strains transformed with high copy number plasmids carrying the gene encoding a green fluorescent protein optimised for yeast (yEGFP3) under the control of the RAD54 or RNR2 promoter were used to investigate the activity of potentially DNA-damaging substances. The assays were performed on 96-well microtitre plates in the presence of different concentrations of the test substances. The synthesis of GFP protein was measured through the fluorescence signal and cell growth was monitored by absorption. Here, we demonstrate that this system can be used as a biosensor to assess the genotoxic potential of drugs and other chemical substances. The use of microtitre plates will enable full automation of the system and allows the inclusion of internal reference standards in each assay.
Neuroscience Letters | 2003
Katja Preußat; Christian Beetz; Michael Schrey; Robert Kraft; Stefan Wölfl; Rolf Kalff; Stephan Patt
K(+) channels play an important role in glial cell proliferation and are functionally expressed in glial tumors. Because voltage-gated K(+) channel (Kv) subtypes Kv1.3 and Kv1.5 have been shown to contribute to growth-related properties of normal glia rather specifically, we investigated different human glioma samples for the expression of these channel subtypes using reverse transcriptase-PCR. Kv1.5 expression correlated with glioma entities and malignancy grades, i.e. expression was high in astrocytomas, moderate in oligodendrogliomas, and low in glioblastomas. No such correlation was evident for Kv1.3 expression. This study shows a clear differential expression of Kv1.5 in gliomas according to subtype and malignancy grade. This result corresponds to previous data on the expression of voltage-gated sodium channels in gliomas, which likewise showed a low or absent expression of channel subtypes in high-grade tumors.
Journal of Cancer Research and Clinical Oncology | 2000
Joachim H. Clement; Nannette Marr; Anke Meissner; Manuela Schwalbe; Walter Sebald; Kay-Oliver Kliche; K. Höffken; Stefan Wölfl
Abstract Bone morphogenetic proteins (BMPs) are involved in the development of various organs including the mammary gland. They are well-regulated and act in a time-, concentration- and cell-type-specific manner. We found that BMP-2 is expressed in primary breast tumor tissue samples and in breast cancer cell lines. Hybridization of labeled cDNA, obtained from the breast cancer cell line MCF-7, against the Atlas human cDNA expression array revealed differential gene expression depending on BMP-2 treatment. The most prominent changes were observed for the helix-loop-helix proteins Id-1, Id-2 and Id-3. Id-1 expression had increased severalfold after 4 h and was even higher after 24 h. Id-2 and Id-3 were more strongly induced after 4 h and showed no further significant change after 24 h. Analysis of cell-cycle distribution revealed a marked increase of the sub-G1 phase after 48 h in serum-deprived cells. In the presence of BMP-2 no change was observed over 48 h indicating that BMP-2 does not induce apoptosis. In addition, expression of caspase-3 was reduced in BMP-2-treated cells after 24 h. In summary, our results clearly indicate that BMP-2 is a susceptibility factor keeping the cells ready for the integration of various other signals for cell progression.