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- 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.
- ItemArgon Plasma Exposure Augments Costimulatory Ligands and Cytokine Release in Human Monocyte-Derived Dendritic Cells(Basel : Molecular Diversity Preservation International (MDPI), 2021) Bekeschus, Sander; Meyer, Dorothee; Arlt, Kevin; von Woedtke, Thomas; Miebach, Lea; Freund, Eric; Clemen, RamonaCold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with an immunological dimension, successful antigen presentation and inflammation modulation is a key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However, the inflammatory consequences of DCs following plasma exposure are unknown. To this end, human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes; exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used. Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether, this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in human moDCs, which might exert beneficial effects in the tumor microenvironment.
- ItemDevelopment of an electrochemical sensor for in-situ monitoring of reactive species produced by cold physical plasma(Amsterdam [u.a.] : Elsevier Science, 2021) Nasri, Zahra; Bruno, Giuliana; Bekeschus, Sander; Weltmann, Klaus-Dieter; von Woedtke, Thomas; Wende, KristianThe extent of clinical applications of oxidative stress-based therapies such as photodynamic therapy (PDT) or respiratory chain disruptors are increasing rapidly, with cold physical plasma (CPP) emerging as a further option. According to the current knowledge, the biological effects of CPP base on reactive oxygen and nitrogen species (RONS) relevant in cell signaling. To monitor the safety and the biological impact of the CPP, determining the local generation of RONS in the same environment in which they are going to be applied is desirable. Here, for the first time, the development of an electrochemical sensor for the simple, quick, and parallel determination of plasma-generated reactive species is described. The proposed sensor consists of a toluidine blue redox system that is covalently attached to a gold electrode surface. By recording chronoamperometry at different potentials, it is possible to follow the in-situ production of the main long-lived reactive oxygen and nitrogen species like hydrogen peroxide, nitrite, hypochlorite, and chloramine with time. The applicability of this electrochemical sensor for the in-situ assessment of reactive species in redox-based therapies is demonstrated by the precise analysis of hydrogen peroxide dynamics in the presence of blood cancer cells.
- ItemMedical gas plasma augments bladder cancer cell toxicity in preclinical models and patient-derived tumor tissues(Amsterdam [u.a.] : Elsevier, 2022) Gelbrich, Nadine; Miebach, Lea; Berner, Julia; Freund, Eric; Saadati, Fariba; Schmidt, Anke; Stope, Matthias; Zimmermann, Uwe; Burchardt, Martin; Bekeschus, SanderIntroduction: Medical gas plasma therapy has been successfully applied to several types of cancer in preclinical models. First palliative tumor patients suffering from advanced head and neck cancer benefited from this novel therapeutic modality. The gas plasma-induced biological effects of reactive oxygen and nitrogen species (ROS/RNS) generated in the plasma gas phase result in oxidation-induced lethal damage to tumor cells. Objectives: This study aimed to verify these anti-tumor effects of gas plasma exposure on urinary bladder cancer. Methods: 2D cell culture models, 3D tumor spheroids, 3D vascularized tumors grown on the chicken chorion-allantois-membrane (CAM) in ovo, and patient-derived primary cancer tissue gas plasma-treated ex vivo were used. Results: Gas plasma treatment led to oxidation, growth retardation, motility inhibition, and cell death in 2D and 3D tumor models. A marked decline in tumor growth was also observed in the tumors grown in ovo. In addition, results of gas plasma treatment on primary urothelial carcinoma tissues ex vivo highlighted the selective tumor-toxic effects as non-malignant tissue exposed to gas plasma was less affected. Whole-transcriptome gene expression analysis revealed downregulation of tumor-promoting fibroblast growth factor receptor 3 (FGFR3) accompanied by upregulation of apoptosis-inducing factor 2 (AIFm2), which plays a central role in caspase-independent cell death signaling. Conclusion: Gas plasma treatment induced cytotoxicity in patient-derived cancer tissue and slowed tumor growth in an organoid model of urinary bladder carcinoma, along with less severe effects in non-malignant tissues. Studies on the potential clinical benefits of this local and safe ROS therapy are awaited.
- 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.
- ItemCombined toxicity of gas plasma treatment and nanoparticles exposure in melanoma cells in vitro(Basel : MDPI, 2021) Bekeschus, SanderDespite continuous advances in therapy, cancer remains a deadly disease. Over the past years, gas plasma technology emerged as a novel tool to target tumors, especially skin. Another promising anticancer approach are nanoparticles. Since combination therapies are becoming increas-ingly relevant in oncology, both gas plasma treatment and nanoparticle exposure were combined. A series of nanoparticles were investigated in parallel, namely, silica, silver, iron oxide, cerium oxide, titanium oxide, and iron-doped titanium oxide. For gas plasma treatment, the atmospheric pressure argon plasma jet kINPen was utilized. Using three melanoma cell lines, the two murine non-metastatic B16F0 and metastatic B16F10 cells and the human metastatic B-Raf mutant cell line SK-MEL-28, the combined cytotoxicity of both approaches was identified. The combined cytotoxicity of gas plasma treatment and nanoparticle exposure was consistent across all three cell lines for silica, silver, iron oxide, and cerium oxide. In contrast, for titanium oxide and iron-doped titanium oxide, significantly combined cytotoxicity was only observed in B16F10 cells.
- 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.
- ItemCold Atmospheric Pressure Plasma in Wound Healing and Cancer Treatment(Basel : MDPI, 2020) Boeckmann, Lars; Schäfer, Mirijam; Bernhardt, Thoralf; Semmler, Marie Luise; Jung, Ole; Ojak, Gregor; Fischer, Tobias; Peters, Kirsten; Nebe, Barbara; Müller-Hilke, Brigitte; Seebauer, Christian; Bekeschus, Sander; Emmert, SteffenPlasma medicine is gaining increasing attention and is moving from basic research into clinical practice. While areas of application are diverse, much research has been conducted assessing the use of cold atmospheric pressure plasma (CAP) in wound healing and cancer treatment—two applications with entirely different goals. In wound healing, a tissue-stimulating effect is intended, whereas cancer therapy aims at killing malignant cells. In this review, we provide an overview of the latest clinical and some preclinical research on the efficacy of CAP in wound healing and cancer therapy. Furthermore, we discuss the current understanding of molecular signaling mechanisms triggered by CAP that grant CAP its antiseptic and tissue regenerating or anti-proliferative and cell death-inducing properties. For the efficacy of CAP in wound healing, already substantial evidence from clinical studies is available, while evidence for therapeutic effects of CAP in oncology is mainly from in vitro and in vivo animal studies. Efforts to elucidate the mode of action of CAP suggest that different components, such as ultraviolet (UV) radiation, electromagnetic fields, and reactive species, may act synergistically, with reactive species being regarded as the major effector by modulating complex and concentration-dependent redox signaling pathways.
- 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)
- ItemMedical Gas Plasma Treatment in Head and Neck Cancer—Challenges and Opportunities(Basel : MDPI, 2020) Berner, Julia; Seebauer, Christian; Sagwal, Sanjeev Kumar; Boeckmann, Lars; Emmert, Steffen; Metelmann, Hans-Robert; Bekeschus, SanderDespite progress in oncotherapy, cancer is still among the deadliest diseases in the Western world, emphasizing the demand for novel treatment avenues. Cold physical plasma has shown antitumor activity in experimental models of, e.g., glioblastoma, colorectal cancer, breast carcinoma, osteosarcoma, bladder cancer, and melanoma in vitro and in vivo. In addition, clinical case reports have demonstrated that physical plasma reduces the microbial contamination of severely infected tumor wounds and ulcerations, as is often seen with head and neck cancer patients. These antimicrobial and antitumor killing properties make physical plasma a promising tool for the treatment of head and neck cancer. Moreover, this type of cancer is easily accessible from the outside, facilitating the possibility of several rounds of topical gas plasma treatment of the same patient. Gas plasma treatment of head and neck cancer induces diverse effects via the deposition of a plethora of reactive oxygen and nitrogen species that mediate redox-biochemical processes, and ultimately, selective cancer cell death. The main advantage of medical gas plasma treatment in oncology is the lack of adverse events and significant side effects compared to other treatment modalities, such as surgical approaches, chemotherapeutics, and radiotherapy, making plasma treatment an attractive strategy for the adjuvant and palliative treatment of head and neck cancer. This review outlines the state of the art and progress in investigating physical plasma as a novel treatment modality in the therapy of head and neck squamous cell carcinoma.