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- ItemCombined In Vitro Toxicity and Immunogenicity of Cold Plasma and Pulsed Electric Fields(Basel : MDPI, 2022) Wolff, Christina M.; Kolb, Juergen F.; Bekeschus, SanderIn modern oncology, therapies are based on combining monotherapies to overcome treatment resistance and increase therapy precision. The application of microsecond-pulsed electric fields (PEF) is approved to enhance local chemotherapeutic drug uptake within combination electrochemotherapy regimens. Reactive oxygen species (ROS) have been implicated in anticancer effects, and cold physical plasma produces vast amounts of ROS, which have recently been shown to benefit head and neck cancer patients. PEF and cold plasma technology have been linked to immunogenic cell death (ICD) induction, a regulated cell death accompanied by sterile inflammation that promotes antitumor immunity. To this end, we investigated the combined effect of both treatments regarding their intracellular ROS accumulation, toxicity, ICD-related marker expression, and optimal exposure sequence in a leukemia model cell line. The combination treatment substantially increased ROS and intracellular glutathione levels, leading to additive cytotoxic effects accompanied by a significantly increased expression of ICD markers, such as the eat-me signal calreticulin (CRT). Preconditioned treatment with cold plasma followed by PEF exposure was the most potent treatment sequence. The results indicate additive effects of cold plasma and PEF, motivating further studies in skin and breast tumor models for the future improvement of ECT in such patients.
- 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.
- ItemCell stimulation versus cell death induced by sequential treatments with pulsed electric fields and cold atmospheric pressure plasma(San Francisco, California, US : PLOS, 2018) Steuer, Anna; Wolff, Christina M.; von Woedtke, Thomas; Weltmann, Klaus-Dieter; Kolb, Juergen F.Pulsed electric fields (PEFs) and cold atmospheric pressure plasma (CAP) are currently both investigated for medical applications. The exposure of cells to PEFs can induce the formation of pores in cell membranes and consequently facilitate the uptake of molecules. In contrast, CAP mainly acts through reactive species that are generated in the liquid environment. The objective of this study was to determine, if PEFs combined with plasma-treated cell culture medium can mutually reinforce effects on viability of mammalian cells. Experiments were conducted with rat liver epithelial WB-F344 cells and their tumorigenic counterpart WB-ras for a direct comparison of non-tumorigenic and tumorigenic cells from the same origin. Viability after treatments strongly depended on cell type and applied field strength. Notably, tumorigenic WB-ras cells responded more sensitive to the respective treatments than non-tumorigenic WB-F344 cells. More cells were killed when plasma-treated medium was applied first in combination with treatments with 100-μs PEFs. For the reversed treatment order, i.e. application of PEFs first, the combination with 100-ns PEFs resulted in a stimulating effect for non-tumorigenic but not for tumorigenic cells. The results suggest that other mechanisms, besides simple pore formation, contributed to the mutually reinforcing effects of the two methods.
- ItemSynergistic In Vitro Anticancer Toxicity of Pulsed Electric Fields and Glutathione(Basel : Molecular Diversity Preservation International (MDPI), 2022) Wolff, Christina M.; Bekeschus, SanderDespite continuous advancement in skin cancer therapy, the disease is still fatal in many patients, demonstrating the need to improve existing therapies, such as electrochemotherapy (ECT). ECT can be applied in the palliative or curative setting and is based on the application of pulsed electric fields (PEF), which by themselves exerts none to low cancer toxicity but become potently toxic when combined with low-dosed chemotherapeutics such as bleomycin and cisplatin. Albeit their favorable side-effect profiles, not all patients respond to standard ECT, and some responders experience tumor recurrence. To identify potential adjuvant or alternative agents to standard electrochemotherapy, we explored the possibility of combining PEF with a physiological compound, glutathione (GSH), to amplify anticancer toxicity. GSH is an endogenous antioxidant and is available as a dietary supplement. Surprisingly, neither GSH nor PEF mono treatment but GSH + PEF combination treatment exerted strong cytotoxic effects and declined metabolic activity in four skin cancer cell lines in vitro. The potential applicability to other tumor cells was verified by corroborating results in two leukemia cell lines. Strikingly, GSH + PEF treatment did not immediately increase intracellular GSH levels, while levels 24 h following treatment were enhanced. Similar tendencies were made for intracellular reactive oxygen species (ROS) levels, while extracellular ROS increased following combination treatment. ROS levels and the degree of cytotoxicity could be partially reversed by pre-incubating cells with the NADPH-oxidase (NOX) inhibitor diphenyleneiodonium (DPI) and the H2O2-degrading enzyme catalase. Collectively, our findings suggest a promising new “endogenous” drug to be combined with PEF for future anticancer research approaches.