10 results
Search Results
Now showing 1 - 10 of 10
- ItemCold Atmospheric Plasma in the Treatment of Osteosarcoma(Basel : Molecular Diversity Preservation International, 2017-9-19) Gümbel, Denis; Bekeschus, Sander; Gelbrich, Nadine; Napp, Matthias; Ekkernkamp, Axel; Kramer, Axel; Stope, Matthias B.Human osteosarcoma (OS) is the most common primary malignant bone tumor occurring most commonly in adolescents and young adults. Major improvements in disease-free survival have been achieved by implementing a combination therapy consisting of radical surgical resection of the tumor and systemic multi-agent chemotherapy. However, long-term survival remains poor, so novel targeted therapies to improve outcomes for patients with osteosarcoma remains an area of active research. This includes immunotherapy, photodynamic therapy, or treatment with nanoparticles. Cold atmospheric plasma (CAP), a highly reactive (partially) ionized physical state, has been shown to inherit a significant anticancer capacity, leading to a new field in medicine called “plasma oncology.” The current article summarizes the potential of CAP in the treatment of human OS and reviews the underlying molecular mode of action.
- ItemCold argon plasma as adjuvant tumour therapy on progressive head and neck cancer: A preclinical study(Basel : MDPI, 2019) Hasse, Sybille; Seebauer, Christian; Wende, Kristian; Schmidt, Anke; Metelmann, Hans-Robert; Woedtke, Thomas von; Bekeschus, SanderInvestigating cold argon plasma (CAP) for medical applications is a rapidly growing, innovative field of research. The controllable supply of reactive oxygen and nitrogen species through CAP has the potential for utilization in tumour treatment. Maxillofacial surgery is limited if tumours grow on vital structures such as the arteria carotis. Here CAP could be considered as an option for adjuvant intraoperative tumour therapy especially in the case of squamous cell carcinoma of the head and neck. Further preclinical research is necessary to investigate the efficacy of this technology for future clinical applications in cancer treatment. Initially, a variety of in vitro assays was performed on two cell lines that served as surrogate for the squamous cell carcinoma (SCC) and healthy tissue, respectively. Cell viability, motility and the activation of apoptosis in SCC cells (HNO97) was compared with those in normal HaCaT keratinocytes. In addition, induction of apoptosis in ex vivo CAP treated human tissue biopsies of patients with tumours of the head and neck was monitored and compared to healthy control tissue of the same patient. In response to CAP treatment, normal HaCaT keratinocytes differed significantly from their malignant counterpart HNO97 cells in cell motility only whereas cell viability remained similar. Moreover, CAP treatment of tumour tissue induced more apoptotic cells than in healthy tissue that was accompanied by elevated extracellular cytochrome c levels. This study promotes a future role of CAP as an adjuvant intraoperative tumour therapy option in the treatment of head and neck cancer. Moreover, patient-derived tissue explants complement in vitro examinations in a meaningful way to reflect an antitumoral role of CAP. © 2019 by the authors.
- ItemActivation of murine immune cells upon co-culture with plasma-treated B16F10 melanoma cells(Basel : MDPI, 2019) Rödder, Katrin; Moritz, Juliane; Miller, Vandana; Weltmann, Klaus-Dieter; Metelmann, Hans-Robert; Gandhirajan, Rajesh; Bekeschus, SanderRecent advances in melanoma therapy increased median survival in patients. However, death rates are still high, motivating the need of novel avenues in melanoma treatment. Cold physical plasma expels a cocktail of reactive species that have been suggested for cancer treatment. High species concentrations can be used to exploit apoptotic redox signaling pathways in tumor cells. Moreover, an immune-stimulatory role of plasma treatment, as well as plasma-killed tumor cells, was recently proposed, but studies using primary immune cells are scarce. To this end, we investigated the role of plasma-treated murine B16F10 melanoma cells in modulating murine immune cells' activation and marker profile. Melanoma cells exposed to plasma showed reduced metabolic and migratory activity, and an increased release of danger signals (ATP, CXCL1). This led to an altered cytokine profile with interleukin-1β (IL-1β) and CCL4 being significantly increased in plasma-treated mono- and co-cultures with immune cells. In T cells, plasma-treated melanoma cells induced extracellular signal-regulated Kinase (ERK) phosphorylation and increased CD28 expression, suggesting their activation. In monocytes, CD115 expression was elevated as a marker for activation. In summary, here we provide proof of concept that plasma-killed tumor cells are recognized immunologically, and that plasma exerts stimulating effects on immune cells alone. © 2019 by the authors.
- 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
- 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.
- ItemA Comparison of Floating-Electrode DBD and kINPen Jet: Plasma Parameters to Achieve Similar Growth Reduction in Colon Cancer Cells Under Standardized Conditions(Dordrecht : Springer Science + Business Media B.V., 2017-9-6) Bekeschus, Sander; Lin, Abraham; Fridman, Alexander; Wende, Kristian; Weltmann, Klaus-Dieter; Miller, VandanaA comparative study of two plasma sources (floating-electrode dielectric barrier discharge, DBD, Drexel University; atmospheric pressure argon plasma jet, kINPen, INP Greifswald) on cancer cell toxicity was performed. Cell culture protocols, cytotoxicity assays, and procedures for assessment of hydrogen peroxide (H2O2) were standardized between both labs. The inhibitory concentration 50 (IC50) and its corresponding H2O2 deposition was determined for both devices. For the DBD, IC50 and H2O2 generation were largely dependent on the total energy input but not pulsing frequency, treatment time, or total number of cells. DBD cytotoxicity could not be replicated by addition of H2O2 alone and was inhibited by larger amounts of liquid present during the treatment. Jet plasma toxicity depended on peroxide generation as well as total cell number and amount of liquid. Thus, the amount of liquid present during plasma treatment in vitro is key in attenuating short-lived species or other physical effects from plasmas. These in vitro results suggest a role of liquids in or on tissues during plasma treatment in a clinical setting. Additionally, we provide a platform for correlation between different plasma sources for a predefined cellular response.
- ItemOne Year Follow-Up Risk Assessment in SKH-1 Mice and Wounds Treated with an Argon Plasma Jet(Basel : Molecular Diversity Preservation International, 2017-4-19) Schmidt, Anke; von Woedtke, Thomas; Stenzel, Jan; Lindner, Tobias; Polei, Stefan; Vollmar, Brigitte; Bekeschus, SanderMultiple evidence in animal models and in humans suggest a beneficial role of cold physical plasma in wound treatment. Yet, risk assessment studies are important to further foster therapeutic advancement and acceptance of cold plasma in clinics. Accordingly, we investigated the long-term side effects of repetitive plasma treatment over 14 consecutive days in a rodent full-thickness ear wound model. Subsequently, animals were housed for 350 days and sacrificed thereafter. In blood, systemic changes of the pro-inflammatory cytokines interleukin 1β and tumor necrosis factor α were absent. Similarly, tumor marker levels of α-fetoprotein and calcitonin remained unchanged. Using quantitative PCR, the expression levels of several cytokines and tumor markers in liver, lung, and skin were found to be similar in the control and treatment group as well. Likewise, histological and immunohistochemical analysis failed to detect abnormal morphological changes and the presence of tumor markers such as carcinoembryonic antigen, α-fetoprotein, or the neighbor of Punc 11. Absence of neoplastic lesions was confirmed by non-invasive imaging methods such as anatomical magnetic resonance imaging and positron emission tomography-computed tomography. Our results suggest that the beneficial effects of cold plasma in wound healing come without apparent side effects including tumor formation or chronic inflammation.
- ItemRedox for Repair: Cold Physical Plasmas and Nrf2 Signaling Promoting Wound Healing(Basel : MDPI, 2018-10-19) Schmidt, Anke; Bekeschus, SanderChronic wounds and ulcers are major public health threats. Being a substantial burden for patients and health care systems alike, better understanding of wound pathophysiology and new avenues in the therapy of chronic wounds are urgently needed. Cold physical plasmas are particularly effective in promoting wound closure, irrespective of its etiology. These partially ionized gases deliver a therapeutic cocktail of reactive oxygen and nitrogen species safely at body temperature and without genotoxic side effects. This field of plasma medicine reanimates the idea of redox repair in physiological healing. This review compiles previous findings of plasma effects in wound healing. It discusses new links between plasma treatment of cells and tissues, and the perception and intracellular translation of plasma-derived reactive species via redox signaling pathways. Specifically, (i) molecular switches governing redox-mediated tissue response; (ii) the activation of the nuclear E2-related factor (Nrf2) signaling, together with antioxidative and immunomodulatory responses; and (iii) the stabilization of the scaffolding function and actin network in dermal fibroblasts are emphasized in the light of wound healing.
- 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.
- ItemHmox1 Upregulation Is a Mutual Marker in Human Tumor Cells Exposed to Physical Plasma-Derived Oxidants(Basel : MDPI, 2018-10-27) Bekeschus, Sander; Freund, Eric; Wende, Kristian; Gandhirajan, Rajesh; Schmidt, AnkeIncreasing numbers of cancer deaths worldwide demand for new treatment avenues. Cold physical plasma is a partially ionized gas expelling a variety of reactive oxygen and nitrogen species, which can be harnesses therapeutically. Plasmas and plasma-treated liquids have antitumor properties in vitro and in vivo. Yet, global response signatures to plasma treatment have not yet been identified. To this end, we screened eight human cancer cell lines to investigate effects of low-dose, tumor-static plasma-treated medium (PTM) on cellular activity, immune-modulatory properties, and transcriptional levels of 22 redox-related genes. With PTM, a moderate reduction of metabolic activity and modest modulation of chemokine/cytokine pattern and markers of immunogenic cell death was observed. Strikingly, the Nuclear factor (erythroid-derived 2)-like 2 (nrf2) target heme oxygenase 1 (hmox1) was upregulated in all cell lines 4 h post PTM-treatment. nrf2 was not changed, but its baseline expression inversely and significantly correlated with hmox1 expression after exposure to PTM. Besides awarding hmox1 a central role with plasma-derived oxidants, we present a transcriptional redox map of 22 targets and chemokine/cytokine secretion map of 13 targets across eight different human tumor cell lines of four tumor entities at baseline activity that are useful for future studies in this field.