Lisa Wolff

Universität Greifswald

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Patrick J. Bednarski

Universität Greifswald

Carola Schulzke

Universität Greifswald

Siva Sankar Murthy Bandaru

Universität Greifswald

Martin Napierkowski

Universität Greifswald

Steven Behnisch‐Cornwell

Universität Greifswald

Elias Eger

Helmholtz Centre for Infection Research

Daniel Baecker

Freie Universität Berlin

Hoai-Nhi Lam

Universität Greifswald

Franciszek Sączewski

Gdańsk Medical University

Christopher Horst Lillig

Universitätsmedizin Greifswald

Cooperative Institutions

Ludwig-Maximilians-Universität München

Helmholtz Zentrum München

German Center for Lung Research

Technical University of Munich

Universität Greifswald

Institute of Medical Microbiology and Hygiene

Asklepios Fachkliniken München-Gauting

LMU Klinikum

Gdańsk Medical University

Universitätsmedizin Greifswald

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CCDC 1858786: Experimental Crystal Structure Determination

The Cambridge Structural Database (2020)

Steven Behnisch‐Cornwell Siva Sankar Murthy Bandaru Martin Napierkowski Lisa Wolff Muhammad Zubair

10.5517/ccdc.csd.cc20d6vh

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Citations (0)

Comprehensive Evaluation of Biological Effects of Pentathiepins on Various Human Cancer Cell Lines and Insights into Their Mode of Action

International Journal of Molecular Sciences (2021)

Lisa Wolff Siva Sankar Murthy Bandaru Elias Eger Hoai-Nhi Lam Martin Napierkowski

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future.

GPX1

Mode of Action

10.3390/ijms22147631

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Citations (8)

Front Cover: Pentathiepins: A Novel Class of Glutathione Peroxidase 1 Inhibitors that Induce Oxidative Stress, Loss of Mitochondrial Membrane Potential and Apoptosis in Human Cancer Cells (ChemMedChem 16/2020)

ChemMedChem (2020)

Steven Behnisch‐Cornwell Siva Sankar Murthy Bandaru Martin Napierkowski Lisa Wolff Muhammad Zubair

The Front Cover shows pentathiepins racing to block the enzyme glutathione peroxidase 1 (GPx1), a key defense of tumor cells to cytotoxic hydrogen peroxide, which forms during chemotherapy. In an allegorical depiction, the tumor planet Oncos is under attack from hydrogen peroxide bombs, but these are quickly reduced to harmless water by the defending GPx1 destroyers. However, support is on the way as a group of pentathiepin fighters moves in to neutralize GPx1 and give hydrogen peroxide a chance to destroy Oncos. Already, comets of apoptotic cancer cells are flaming into outer space. More information can be found in the Full Paper by Patrick J. Bednarski et al.

GPX1

Front cover

10.1002/cmdc.202000577

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Synthesis and cytotoxic evaluation of benzoxazole/benzothiazole-2-imino-coumarin hybrids and their coumarin analogues as potential anticancer agents.

PubMed (2019)

Anna Makowska Lisa Wolff Franciszek Sa̧czewski Patrick J. Bednarski Anita Kornicka

Two series of 2-imino-coumarin based hybrids: 3-(benzoxazol-2-yl)-2H-chromen-2-imines 3-9 (series A-I) and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 10-16 (series A-II), as well as their coumarin analogues: 3-(benzoxazol-2-yl)-2H-chromen-2-ones 17-21 (series B-I) and 3-(benzothiazol-2-yl)-2H-chromen-2-ones 22-28 (series B-II) were prepared as potential antitumor agents. The in vitro cytotoxic potency of the synthesized compounds was evaluated against five human cancer cell lines: DAN-G, A-427, LCLC-103H, RT-4 and SISO, and relationships between structure and anticancer activity are discussed. Among the compounds tested, 3-(benzo[d] oxazol-2-yl)-N,N-diethyl-2-imino-2H-chromen-7-amine (6, series A-I) and 3-(benzo[d]thiazol-2-yl)-6-fluoro-2H-chromen-2-one (26, series B-II) exhibited the most potent cytotoxic activity with IC50 values ranging from <0.01 μM to 1.1 μM. In particular, compound 6 demonstrated remarkable cytotoxicity against the A-427 ovarian cancer, the lung cancer LCLC-103H, urinary bladder cancer RT-4 and cervical cancer SISO cell lines with IC50 <0.01-0.30μM, inducing apoptosis in two representative cell lines.

Benzothiazole

Benzoxazole

IC50

10.1691/ph.2019.9664

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Citations (17)

Synthesis, Structure and Cytotoxicity Testing of Novel 7-(4,5-Dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives

Molecules (2020)

Łukasz Balewski Franciszek Sa̧czewski Patrick J. Bednarski Lisa Wolff Anna Nadworska

The appropriate 1-arylhydrazinecarbonitriles 1a–c are subjected to the reaction with 2-chloro-4,5-dihydro-1H-imidazole (2), yielding 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-imines 3a–c, which are subsequently converted into the corresponding amides 4a–e, 8a–c, sulfonamides 5a–n, 9, ureas 6a–I, and thioureas 7a–d. The structures of the newly prepared derivatives 3a–c, 4a–e, 5a–n, 6a–i, 7a–d, 8a–c, and 9 are confirmed by IR, NMR spectroscopic data, as well as single-crystal X-ray analyses of 5e and 8c. The in vitro cytotoxic potency of these compounds is determined on a panel of human cancer cell lines, and the relationships between structure and antitumor activity are discussed. The most active 4-chloro-N-(2-(4-chlorophenyl)-7-(4,5-dihydro-1H-imidazol-2-yl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)benzamide (4e) and N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-[1,1′-biphenyl]-4-sulfonamide (5l) inhibits the growth of the cervical cancer SISO and bladder cancer RT-112 cell lines with IC50 values in the range of 2.38–3.77 μM. Moreover, N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-phenyl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-4-phenoxybenzenesulfonamide (5m) has the best selectivity towards the SISO cell line and induces apoptosis in this cell line.

Benzamide

Imine

Imidazole

Sulfonamide

10.3390/molecules25245924

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Citations (6)

The Effect of Glutathione Peroxidase-1 Knockout on Anticancer Drug Sensitivities and Reactive Oxygen Species in Haploid HAP-1 Cells

Antioxidants (2020)

Steven Behnisch‐Cornwell Lisa Wolff Patrick J. Bednarski

The role of glutathione peroxidases (GPx) in cancer and their influence on tumor prognosis and the development of anticancer drug resistance has been extensively and controversially discussed. The aim of this study was to evaluate the influence of GPx1 expression on anticancer drug cytotoxicity. For this purpose, a GPx1 knockout of the near-haploid human cancer cell line HAP-1 was generated and compared to the native cell line with regards to morphology, growth and metabolic rates, and oxidative stress defenses. Furthermore, the IC50 values of two peroxides and 16 widely used anticancer drugs were determined in both cell lines. Here we report that the knockout of GPx1 in HAP-1 cells has no significant effect on cell size, viability, growth and metabolic rates. Significant increases in the cytotoxic potency of hydrogen peroxide and tert-butylhydroperoxide, the anticancer drugs cisplatin and carboplatin as well as the alkylating agents lomustine and temozolomide were found. While a concentration dependent increases in intracellular reactive oxygen species (ROS) levels were observed for both HAP-1 cell lines treated with either cisplatin, lomustine or temozolamide, no significant enhancement in ROS levels was observed in the GPx1 knockout compared to the native cell line except at the highest concentration of temozolamide. On the other hand, a ca. 50% decrease in glutathione levels was noted in the GPx1 knockout relative to the native line, suggesting that factors other than ROS levels alone play a role in the increased cytotoxic activity of these drugs in the GPx1 knockout cells.

GPX1

Growth inhibition

10.3390/antiox9121300

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Citations (12)

Acceleration of apoptosis in transforming growth factor beta 1-treated M1 cells ectopically expressing B-myb.

PubMed (1995)

Juraj Bies Lisa Wolff

Inappropriate expression of genes involved in cell proliferation can result in altered regulation of apoptosis, a process of programmed cell death. Since B-myb has recently been implicated in the cell cycle progression we wanted to examine its role in the apoptotic process. For this purpose we used transforming growth factor beta 1 (TGF-beta 1)-treated M1 myeloid leukemia cell lines that continuously express murine B-myb. It was found that in cells overexpressing B-myb, TGF-beta 1-induced apoptosis was accelerated as assessed by cell viability and DNA fragmentation into nucleosomal fragments. A DNA ladder was detected after 24 h of TGF-beta 1 treatment in these cells, whereas it was not detected until after 36 h in the parental M1 cells. It was further determined by Northern blot analysis that this higher sensitivity of B-myb overexpressing clones was not due to a change in the expression of TGF-beta receptor type I or in the kinetics of the regulation of c-myc, c-myb, bcl-2, and/or bax.

MYB

Viability assay

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Citations (28)

Single-cell RNA sequencing reveals ex vivo signatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’

Nature Communications (2021)

David S. Fischer Meshal Ansari K Wagner Sebastian Jarosch Yiqi Huang

The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we use single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induce transcriptional shifts by antigenic stimulation in vitro and take advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for 'reverse phenotyping'. This allows identification of SARS-CoV-2-reactive TCRs and reveals phenotypic effects introduced by antigen-specific stimulation. We characterize transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and show correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.

Ex vivo

10.1038/s41467-021-24730-4

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Citations (30)

CCDC 2079766: Experimental Crystal Structure Determination

The Cambridge Structural Database (2021)

Lisa Wolff Siva Sankar Murthy Bandaru Elias Eger Hoai-Nhi Lam Martin Napierkowski

10.5517/ccdc.csd.cc27t57h

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Single-cell RNA sequencing revealsin vivosignatures of SARS-CoV-2-reactive T cells through ‘reverse phenotyping’

medRxiv (Cold Spring Harbor Laboratory) (2020)

David S. Fischer Meshal Ansari K Wagner Sebastian Jarosch Yiqi Huang

ABSTRACT The in vivo phenotypic profile of T cells reactive to severe acute respiratory syndrome (SARS)-CoV-2 antigens remains poorly understood. Conventional methods to detect antigen-reactive T cells require in vitro antigenic re-stimulation or highly individualized peptide-human leukocyte antigen (pHLA) multimers. Here, we used single-cell RNA sequencing to identify and profile SARS-CoV-2-reactive T cells from Coronavirus Disease 2019 (COVID-19) patients. To do so, we induced transcriptional shifts by antigenic stimulation in vitro and took advantage of natural T cell receptor (TCR) sequences of clonally expanded T cells as barcodes for ‘reverse phenotyping’. This allowed identification of SARS-CoV-2-reactive TCRs and revealed phenotypic effects introduced by antigen-specific stimulation. We characterized transcriptional signatures of currently and previously activated SARS-CoV-2-reactive T cells, and showed correspondence with phenotypes of T cells from the respiratory tract of patients with severe disease in the presence or absence of virus in independent cohorts. Reverse phenotyping is a powerful tool to provide an integrated insight into cellular states of SARS-CoV-2-reactive T cells across tissues and activation states.

10.1101/2020.12.07.20245274

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Citations (3)