@article{GrebinykPrylutskaBuchelnikovetal.2019,
  author    = {Grebinyk, Anna and Prylutska, Svitlana and Buchelnikov, Anatoliy and Tverdokhleb, Nina and Grebinyk, Sergii and Evstigneev, Maxim and Matyshevska, Olga and Cherepanov, Vsevolod and Prylutskyy, Yuriy and Yashchuk, Valeriy and Naumovets, Anton and Ritter, Uwe and Dandekar, Thomas and Frohme, Marcus},
  title     = {C60 fullerene as an effective nanoplatform of alkaloid Berberine delivery into leukemic cells},
  series = {Pharmaceutics},
  volume    = {11},
  journal   = {Pharmaceutics},
  number    = {11},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics11110586},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193216},
  pages     = {586},
  year      = {2019},
  abstract  = {A herbal alkaloid Berberine (Ber), used for centuries in Ayurvedic, Chinese, Middle-Eastern, and native American folk medicines, is nowadays proved to function as a safe anticancer agent. Yet, its poor water solubility, stability, and bioavailability hinder clinical application. In this study, we have explored a nanosized carbon nanoparticle—C60 fullerene (C60)—for optimized Ber delivery into leukemic cells. Water dispersions of noncovalent C60-Ber nanocomplexes in the 1:2, 1:1, and 2:1 molar ratios were prepared. UV-Vis spectroscopy, dynamic light scattering (DLS), and atomic force microscopy (AFM) evidenced a complexation of the Ber cation with the negatively charged C60 molecule. The computer simulation showed that π-stacking dominates in Ber and C\(_{60}\) binding in an aqueous solution. Complexation with C\(_{60}\) was found to promote Ber intracellular uptake. By increasing C\(_{60}\) concentration, the C\(_{60}\)-Ber nanocomplexes exhibited higher antiproliferative potential towards CCRF-CEM cells, in accordance with the following order: free Ber < 1:2 < 1:1 < 2:1 (the most toxic). The activation of caspase 3/7 and accumulation in the sub-G1 phase of CCRF-CEM cells treated with C\(_{60}\)-Ber nanocomplexes evidenced apoptosis induction. Thus, this study indicates that the fast and easy noncovalent complexation of alkaloid Ber with C\(_{60}\) improved its in vitro efficiency against cancer cells.},
  language  = {en}
}
@article{BartelPeinPopperetal.2019,
  author    = {Bartel, Karin and Pein, Helmut and Popper, Bastian and Schmitt, Sabine and Janaki-Raman, Sudha and Schulze, Almut and Lengauer, Florian and Koeberle, Andreas and Werz, Oliver and Zischka, Hans and M{\"u}ller, Rolf and Vollmar, Angelika M. and Schwarzenberg, Karin von},
  title     = {Connecting lysosomes and mitochondria - a novel role for lipid metabolism in cancer cell death},
  series = {Cell Communication and Signaling},
  volume    = {17},
  journal   = {Cell Communication and Signaling},
  doi       = {10.1186/s12964-019-0399-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221524},
  year      = {2019},
  abstract  = {Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors.},
  language  = {en}
}
@article{FathyFawzyHintzscheetal.2019,
  author    = {Fathy, Moustafa and Fawzy, Michael Atef and Hintzsche, Henning and Nikaido, Toshio and Dandekar, Thomas and Othman, Eman M.},
  title     = {Eugenol exerts apoptotic effect and modulates the sensitivity of HeLa cells to cisplatin and radiation},
  series = {Molecules},
  volume    = {24},
  journal   = {Molecules},
  number    = {21},
  issn      = {1420-3049},
  doi       = {10.3390/molecules24213979},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193227},
  pages     = {3979},
  year      = {2019},
  abstract  = {Eugenol is a phytochemical present in different plant products, e.g., clove oil. Traditionally, it is used against a number of different disorders and it was suggested to have anticancer activity. In this study, the activity of eugenol was evaluated in a human cervical cancer (HeLa) cell line and cell proliferation was examined after treatment with various concentrations of eugenol and different treatment durations. Cytotoxicity was tested using lactate dehydrogenase (LDH) enzyme leakage. In order to assess eugenol's potential to act synergistically with chemotherapy and radiotherapy, cell survival was calculated after eugenol treatment in combination with cisplatin and X-rays. To elucidate its mechanism of action, caspase-3 activity was analyzed and the expression of various genes and proteins was checked by RT-PCR and western blot analyses. Eugenol clearly decreased the proliferation rate and increased LDH release in a concentration- and time-dependent manner. It showed synergistic effects with cisplatin and X-rays. Eugenol increased caspase-3 activity and the expression of Bax, cytochrome c (Cyt-c), caspase-3, and caspase-9 and decreased the expression of B-cell lymphoma (Bcl)-2, cyclooxygenase-2 (Cox-2), and interleukin-1 beta (IL-1β) indicating that eugenol mainly induced cell death by apoptosis. In conclusion, eugenol showed antiproliferative and cytotoxic effects via apoptosis and also synergism with cisplatin and ionizing radiation in the human cervical cancer cell line.},
  language  = {en}
}
@article{Wajant2019,
  author    = {Wajant, Harald},
  title     = {Molecular mode of action of TRAIL receptor agonists—common principles and their translational exploitation},
  series = {Cancers},
  volume    = {11},
  journal   = {Cancers},
  number    = {7},
  doi       = {10.3390/cancers11070954},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202416},
  pages     = {954},
  year      = {2019},
  abstract  = {Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.},
  language  = {en}
}
@article{Wajant2019,
  author    = {Wajant, Harald},
  title     = {Molecular mode of action of TRAIL receptor agonists—common principles and their translational exploitation},
  series = {Cancers},
  volume    = {11},
  journal   = {Cancers},
  number    = {7},
  doi       = {10.3390/cancers11070954},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201833},
  pages     = {954},
  year      = {2019},
  abstract  = {Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors TRAILR1/death receptor 4 (DR4) and TRAILR2/DR5 trigger cell death in many cancer cells but rarely exert cytotoxic activity on non-transformed cells. Against this background, a variety of recombinant TRAIL variants and anti-TRAIL death receptor antibodies have been developed and tested in preclinical and clinical studies. Despite promising results from mice tumor models, TRAIL death receptor targeting has failed so far in clinical studies to show satisfying anti-tumor efficacy. These disappointing results can largely be explained by two issues: First, tumor cells can acquire TRAIL resistance by several mechanisms defining a need for combination therapies with appropriate sensitizing drugs. Second, there is now growing preclinical evidence that soluble TRAIL variants but also bivalent anti-TRAIL death receptor antibodies typically require oligomerization or plasma membrane anchoring to achieve maximum activity. This review discusses the need for oligomerization and plasma membrane attachment for the activity of TRAIL death receptor agonists in view of what is known about the molecular mechanisms of how TRAIL death receptors trigger intracellular cell death signaling. In particular, it will be highlighted which consequences this has for the development of next generation TRAIL death receptor agonists and their potential clinical application.},
  language  = {en}
}
@article{GrebinykPrylutskaChepurnaetal.2019,
  author    = {Grebinyk, Anna and Prylutska, Svitlana and Chepurna, Oksana and Grebinyk, Sergii and Prylutskyy, Yuriy and Ritter, Uwe and Ohulchanskyy, Tymish Y. and Matyshevska, Olga and Dandekar, Thomas and Frohme, Marcus},
  title     = {Synergy of chemo- and photodynamic therapies with C\(_{60}\) Fullerene-Doxorubicin nanocomplex},
  series = {Nanomaterials},
  volume    = {9},
  journal   = {Nanomaterials},
  number    = {11},
  issn      = {2079-4991},
  doi       = {10.3390/nano9111540},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193140},
  year      = {2019},
  abstract  = {A nanosized drug complex was explored to improve the efficiency of cancer chemotherapy, complementing it with nanodelivery and photodynamic therapy. For this, nanomolar amounts of a non-covalent nanocomplex of Doxorubicin (Dox) with carbon nanoparticle C\(_{60}\) fullerene (C\(_{60}\)) were applied in 1:1 and 2:1 molar ratio, exploiting C\(_{60}\) both as a drug-carrier and as a photosensitizer. The fluorescence microscopy analysis of human leukemic CCRF-CEM cells, in vitro cancer model, treated with nanocomplexes showed Dox's nuclear and C\(_{60}\)'s extranuclear localization. It gave an opportunity to realize a double hit strategy against cancer cells based on Dox's antiproliferative activity and C\(_{60}\)'s photoinduced pro-oxidant activity. When cells were treated with 2:1 C\(_{60}\)-Dox and irradiated at 405 nm the high cytotoxicity of photo-irradiated C\(_{60}\)-Dox enabled a nanomolar concentration of Dox and C\(_{60}\) to efficiently kill cancer cells in vitro. The high pro-oxidant and pro-apoptotic efficiency decreased IC\(_{50}\) 16, 9 and 7 × 10\(^3\)-fold, if compared with the action of Dox, non-irradiated nanocomplex, and C\(_{60}\)'s photodynamic effect, correspondingly. Hereafter, a strong synergy of therapy arising from the combination of C\(_{60}\)-mediated Dox delivery and C\(_{60}\) photoexcitation was revealed. Our data indicate that a combination of chemo- and photodynamic therapies with C\(_{60}\)-Dox nanoformulation provides a promising synergetic approach for cancer treatment.},
  language  = {en}
}
@article{ScheurerBrandsElMeseryetal.2019,
  author    = {Scheurer, Mario Joachim Johannes and Brands, Roman Camillus and El-Mesery, Mohamed and Hartmann, Stefan and M{\"u}ller-Richter, Urs Dietmar Achim and K{\"u}bler, Alexander Christian and Seher, Axel},
  title     = {The selection of NFκB inhibitors to block inflammation and induce sensitisation to FasL-induced apoptosis in HNSCC cell lines is critical for their use as a prospective cancer therapy},
  series = {International Journal of Molecular Science},
  volume    = {20},
  journal   = {International Journal of Molecular Science},
  number    = {6},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20061306},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201524},
  year      = {2019},
  abstract  = {Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors — Cortisol, MLN4924, QNZ and TPCA1 — on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low μM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.},
  language  = {en}
}
@article{WajantSiegmund2019,
  author    = {Wajant, Harald and Siegmund, Daniela},
  title     = {TNFR1 and TNFR2 in the control of the life and death balance of macrophages},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {7},
  journal   = {Frontiers in Cell and Developmental Biology},
  number    = {91},
  doi       = {10.3389/fcell.2019.00091},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201551},
  year      = {2019},
  abstract  = {Macrophages stand in the first line of defense against a variety of pathogens but are also involved in the maintenance of tissue homeostasis. To fulfill their functions macrophages sense a broad range of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs) by plasma membrane and intracellular pattern recognition receptors (PRRs). Intriguingly, the overwhelming majority of PPRs trigger the production of the pleiotropic cytokine tumor necrosis factor-alpha (TNF). TNF affects almost any type of cell including macrophages themselves. TNF promotes the inflammatory activity of macrophages but also controls macrophage survival and death. TNF exerts its activities by stimulation of two different types of receptors, TNF receptor-1 (TNFR1) and TNFR2, which are both expressed by macrophages. The two TNF receptor types trigger distinct and common signaling pathways that can work in an interconnected manner. Based on a brief general description of major TNF receptor-associated signaling pathways, we focus in this review on research of recent years that revealed insights into the molecular mechanisms how the TNFR1-TNFR2 signaling network controls the life and death balance of macrophages. In particular, we discuss how the TNFR1-TNFR2 signaling network is integrated into PRR signaling.},
  language  = {en}
}