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- ItemPlasma treatment limits human melanoma spheroid growth and metastasis independent of the ambient gas composition(Basel : MDPI AG, 2020) Hasse, Sybille; Meder, Tita; Freund, Eric; Woedtke, Thomas von; Bekeschus, SanderMelanoma skin cancer is still a deadly disease despite recent advances in therapy. Previous studies have suggested medical plasma technology as a promising modality for melanoma treatment. However, the efficacy of plasmas operated under different ambient air conditions and the comparison of direct and indirect plasma treatments are mostly unexplored for this tumor entity. Moreover, exactly how plasma treatment affects melanoma metastasis has still not been explained. Using 3D tumor spheroid models and high-content imaging technology, we addressed these questions by utilizing one metastatic and one non-metastatic human melanoma cell line targeted with an argon plasma jet. Plasma treatment was toxic in both cell lines. Modulating the oxygen and nitrogen ambient air composition (100/0, 75/25, 50/50, 25/75, and 0/100) gave similar toxicity and reduced the spheroid growth for all conditions. This was the case for both direct and indirect treatments, with the former showing a treatment time-dependent response while the latter resulted in cytotoxicity with the longest treatment time investigated. Live-cell imaging of in-gel cultured spheroids indicated that plasma treatment did not enhance metastasis, and flow cytometry showed a significant modulation of S100A4 but not in any of the five other metastasis-related markers (β-catenin, E-cadherin, LEF1, SLUG, and ZEB1) investigated. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemPlasma treatment limits cutaneous squamous cell carcinoma development in vitro and in vivo(Basel : MDPI AG, 2020) Pasqual-Melo, Gabriella; Nascimento, Thiago; Sanches, Larissa Juliani; Blegniski, Fernanda Paschoal; Bianchi, Julya Karen; Sagwal, Sanjeev Kumar; Berner, Julia; Schmidt, Anke; Emmert, Steffen; Weltmann, Klaus-Dieter; Woedtke, Thomas von; Gandhirajan, Rajesh Kumar; Cecchini, Alessandra Lourenço; Bekeschus, SanderCutaneous squamous cell carcinoma (SCC) is the most prevalent cancer worldwide, increasing the cost of healthcare services and with a high rate of morbidity. Its etiology is linked to chronic ultraviolet (UV) exposure that leads to malignant transformation of keratinocytes. Invasive growth and metastasis are severe consequences of this process. Therapy-resistant and highly aggressive SCC is frequently fatal, exemplifying the need for novel treatment strategies. Cold physical plasma is a partially ionized gas, expelling therapeutic doses of reactive oxygen and nitrogen species that were investigated for their anticancer capacity against SCC in vitro and SCC-like lesions in vivo. Using the kINPen argon plasma jet, a selective growth-reducing action of plasma treatment was identified in two SCC cell lines in 2D and 3D cultures. In vivo, plasma treatment limited the progression of UVB-induced SSC-like skin lesions and dermal degeneration without compromising lesional or non-lesional skin. In lesional tissue, this was associated with a decrease in cell proliferation and the antioxidant transcription factor Nrf2 following plasma treatment, while catalase expression was increased. Analysis of skin adjacent to the lesions and determination of global antioxidant parameters confirmed the local but not systemic action of the plasma anticancer therapy in vivo. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemMolecular mechanisms of the efficacy of cold atmospheric pressure plasma (CAP) in cancer treatment(Basel : MDPI AG, 2020) Semmler, Marie Luise; Bekeschus, Sander; Schäfer, Mirijam; Bernhardt, Thoralf; Fischer, Tobias; Witzke, Katharina; Seebauer, Christian; Rebl, Henrike; Grambow, Eberhard; Vollmar, Brigitte; Nebe, J. Barbara; Metelmann, Hans-Robert; Woedtke, Thomas von; Emmert, Steffen; Boeckmann, LarsRecently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemPlatelets are key in cold physical plasma-facilitated blood coagulation in mice(Amsterdam [u.a.] : Elsevier, 2017) Bekeschus, Sander; Brüggemeier, Janik; Hackbarth, Christine; Woedtke, Thomas von; Partecke, Lars-Ivo; van der Linde, JuliaPurpose: Surgical interventions inevitably lead to destruction of blood vessels. This is especially dangerous in anticoagulated patients. Electrocauterization is a frequently used technique to seal incised tissue. However, leading to a superficial layer of necrotic tissue, the treated area evolves a high vulnerability to contact, making it prone to detachment. As a result, dangerous postoperative bleeding may occur. Cold physical plasma was previously suggested as a pro-coagulant treatment method. It mainly acts by expelling a delicate mixture of oxidants. We therefore tested the suitability of an atmospheric pressure plasma jet (kINPen MED) as a new medical device for sufficient blood coagulation in a murine model of liver incision. Methods: Plasma treatment of murine blood ex vivo induced sufficient coagula. This effect did not affect any tested parameter of plasmatic coagulation cascade, suggesting the mechanism to be related to cellular coagulation. Indeed, isolated platelets were significantly activated following exposure to plasma, although this effect was less pronounced in whole blood. To analyze the biological effect of plasma-on blood coagulation in vivo, mice were anticoagulated (clopidogrel inhibiting cellular and rivaroxaban inhibiting plasmatic hemostasis) or received vehicle only. Afterwards, a partial resection of the left lateral liver lobe was performed. The quantification of the blood loss after liver incision followed by treatment with kINPen MED plasma or electrocauterization revealed a similar and significant hemostatic performance in native and rivaroxaban but not clopidogrel-treated animals compared to argon gas-treated controls. In contrast to electrocauterization, kINPen MED plasma treatment did not cause necrotic cell layers. Conclusion: Our results propose a prime importance of platelets in cold physical plasma-mediated hemostasis and suggest a clinical benefit of kINPen MED plasma treatment as coagulation device in liver surgery.
- ItemCombination treatment with cold physical plasma and pulsed electric fields augments ros production and cytotoxicity in lymphoma(Basel : MDPI AG, 2020) Wolff, Christina M.; Kolb, Juergen F.; Weltmann, Klaus-Dieter; Woedtke, Thomas von; Bekeschus, SanderNew approaches in oncotherapy rely on the combination of different treatments to enhance the efficacy of established monotherapies. Pulsed electric fields (PEFs) are an established method (electrochemotherapy) for enhancing cellular drug uptake while cold physical plasma is an emerging and promising anticancer technology. This study aimed to combine both technologies to elucidate their cytotoxic potential as well as the underlying mechanisms of the effects observed. An electric field generator (0.9–1.0 kV/cm and 100-μs pulse duration) and an atmospheric pressure argon plasma jet were employed for the treatment of lymphoma cell lines as a model system. PEF but not plasma treatment induced cell membrane permeabilization. Additive cytotoxicity was observed for the metabolic activity and viability of the cells while the sequence of treatment in the combination played only a minor role. Intriguingly, a parallel combination was more effective compared to a 15-min pause between both treatment regimens. A combination effect was also found for lipid peroxidation; however, none could be observed in the cytosolic and mitochondrial reactive oxygen species (ROS) production. The supplementation with either antioxidant, a pan-caspase-inhibitor or a ferroptosis inhibitor, all partially rescued lymphoma cells from terminal cell death, which contributes to the mechanistic understanding of this combination treatment. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
- ItemThe molecular and physiological consequences of cold plasma treatment in murine skin and its barrier function(New York, NY [u.a.] : Elsevier, 2020) Schmidt, Anke; Liebelt, Grit; Striesow, Johanna; Freund, Eric; Woedtke, Thomas von; Wende, Kristian; Bekeschus, SanderCold plasma technology is an emerging tool facilitating the spatially controlled delivery of a multitude of reactive species (ROS) to the skin. While the therapeutic efficacy of plasma treatment has been observed in several types of diseases, the fundamental consequences of plasma-derived ROS on skin physiology remain unknown. We aimed to bridge this gap since the epidermal skin barrier and perfusion plays a vital role in health and disease by maintaining homeostasis and protecting from environmental damage. The intact skin of SKH1 mice was plasma-treated in vivo. Gene and protein expression was analyzed utilizing transcriptomics, qPCR, and Western blot. Immunofluorescence aided the analysis of percutaneous skin penetration of curcumin. Tissue oxygenation, perfusion, hemoglobin, and water index was investigated using hyperspectral imaging. Reversed-phase liquid-chromatography/mass spectrometry was performed for the identification of changes in the lipid composition and oxidation. Transcriptomic analysis of plasma-treated skin revealed modulation of genes involved in regulating the junctional network (tight, adherence, and gap junctions), which was confirmed using qPCR, Western blot, and immunofluorescence imaging. Plasma treatment increased the disaggregation of cells in the stratum corneum (SC) concomitant with increased tissue oxygenation, gap junctional intercellular communication, and penetration of the model drug curcumin into the SC preceded by altered oxidation of skin lipids and their composition in vivo. In summary, plasma-derived ROS modify the junctional network, which promoted tissue oxygenation, oxidation of SC-lipids, and restricted penetration of the model drug curcumin, implicating that plasma may provide a novel and sensitive tool of skin barrier regulation. © 2020 The Author(s)
- ItemCan the effect of cold physical plasma-derived oxidants be transported via thiol group oxidation?(Amsterdam [u.a.] : Elsevier, 2019) Heusler, Thea; Bruno, Giuliana; Bekeschus, Sander; Lackmann, Jan-Wilm; Woedtke, Thomas von; Wende, KristianPurpose: Intra- and intercellular redox-signaling processes where found responsible in various physiological and pathological processes with cellular thiol groups as important signal transducers. Using cold atmospheric plasma (CAP), a similar oxidation pattern of thiol groups can be achieved. Hence, it must be clarified which role extracellular thiol groups play in mediating CAP effects and whether or not the effects of short-lived reactive species can be preserved in a molecule like cysteine. Methods: Physiological buffer solutions containing the amino acid cysteine were treated by an MHz argon plasma jet with molecular gas admixtures (kINPen) and transferred to cultured human keratinocytes. Cell proliferation, migratory activity, and metabolism were investigated. High-resolution mass spectrometry was used to estimate the impact of plasma generated species on thiol groups. Results: While treated physiologic cysteine concentrations showed no impact on cell behavior, artificially high concentrations decreased proliferation, migration and lactate secretion. GSH levels inside cells were stabilized. Conclusion: Extracellular thiol groups scavenge plasma-generated species and form a multitude of covalent modifications. Unexpectedly, human keratinocytes show only small functional consequences for treated physiologic cysteine concentrations. Results for high concentrated cysteine solutions indicate an improved cytostatic/cytotoxic impact by plasma treatment suggesting a potential application as a “preserving agent” of the chemical energy of plasma-derived species. © 2019 The Authors
- ItemRisk assessment of kINPen plasma treatment of four human pancreatic cancer cell lines with respect to metastasis(Basel : MDPI AG, 2019) Bekeschus, Sander; Freund, Eric; Spadola, Chiara; Privat-Maldonado, Angela; Hackbarth, Christine; Bogaerts, Annemie; Schmidt, Anke; Wende, Kristian; Weltmann, Klaus-Dieter; Woedtke, Thomas von; Heidecke, Claus-Dieter; Partecke, Lars-Ivo; Käding, AndréCold physical plasma has limited tumor growth in many preclinical models and is, therefore, suggested as a putative therapeutic option against cancer. Yet, studies investigating the cells’ metastatic behavior following plasma treatment are scarce, although being of prime importance to evaluate the safety of this technology. Therefore, we investigated four human pancreatic cancer cell lines for their metastatic behavior in vitro and in chicken embryos (in ovo). Pancreatic cancer was chosen as it is particularly metastatic to the peritoneum and systemically, which is most predictive for outcome. In vitro, treatment with the kINPen plasma jet reduced pancreatic cancer cell activity and viability, along with unchanged or decreased motility. Additionally, the expression of adhesion markers relevant for metastasis was down-regulated, except for increased CD49d. Analysis of 3D tumor spheroid outgrowth showed a lack of plasma-spurred metastatic behavior. Finally, analysis of tumor tissue grown on chicken embryos validated the absence of an increase of metabolically active cells physically or chemically detached with plasma treatment. We conclude that plasma treatment is a safe and promising therapeutic option and that it does not promote metastatic behavior in pancreatic cancer cells in vitro and in ovo. © 2019 by the authors.