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Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. Despite multimodal treatments including surgery, chemotherapy and radiotherapy the prognosis remains poor and relapse occurs regularly. The alkylating agent temozolomide (TMZ) has been shown to improve the overall survival in patients with malignant gliomas, especially in tumors with methylated promoter of the O6-methylguanine-DNA-methyltransferase (MGMT) gene. However, intrinsic and acquired resistance towards TMZ makes it crucial to find new therapeutic strategies aimed at improving the prognosis of patients suffering from malignant gliomas. Cold atmospheric plasma is a new auspicious candidate in cancer treatment. In the present study we demonstrate the anti-cancer properties of different dosages of cold atmospheric plasma (CAP) both in TMZ-sensitive and TMZ-resistant cells by proliferation assay, immunoblotting, cell cycle analysis, and clonogenicity assay. Importantly, CAP treatment restored the responsiveness of resistant glioma cells towards TMZ therapy. Concomitant treatment with CAP and TMZ led to inhibition of cell growth and cell cycle arrest, thus CAP might be a promising candidate for combination therapy especially for patients suffering from GBMs showing an unfavorable MGMT status and TMZ resistance.

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In this study different influences on the bactericidal effect of cold atmospheric plasma (CAP) were investigated intensively. In detail, different initial densities of Escherichia coli cells and different treatment times of up to 8 min were studied. The results show that up to densities of 10 5 cells per 20 µl high reduction rates of up to 5 log can be achieved in less than 3 min of CAP application. In contrast, for higher cell densities almost no reduction was measured for CAP treatment times of up to 8 min. To understand this data in detail, a theoretical model was developed. This model starts from the premise that bacteria are able to some degree to neutralize reactive species and that accordingly the bactericidal effect depends on the bacterial concentration. A further purpose of this study was to analyze the contribution of reactive oxygen and also reactive nitrogen species-produced by the CAP-to the bactericidal effect. We therefore measured nitrites, nitrates and hydrogen peroxide-products of chemical reactions between the species produced by the CAP and the liquid. The evidence of nitric oxide (NO) uptake in bacteria and the corresponding reference experiments with hydrogen peroxide and a chemical NO donor clearly 4

There are conflicting data about localization of poly(ADP-ribose)polymerase-1 and its product poly(ADP-ribose) in mitochondria. To finally clarify the discussion, we investigated with biochemical and cell biological methods the potential presence of poly(ADP-ribose) polymerase-1 in these organelles. Our data show that endogenous and overexpressed poly(ADP-ribose)polymerase 1 is only localized to the nucleus with a clear exclusion of cytosolic compartments. In addition, highly purified mitochondria devoid of nuclear contaminations do not contain poly(ADP-ribose)polymerase-1. Although no poly (ADP-ribose)polymerase-1 enzyme is detectable in mitochondria, a shorter variant of its product poly(ADP-ribose) is present, associated specifically with a small subset of mitochondrial proteins as revealed by immunoprecipitation and protein fingerprint analysis. These proteins are located at key-points of the Krebs-cycle, are chaperones involved in mitochondrial functionality and quality-control, and are RNA-binding proteins important for transcript stability, respectively. Of note, despite the fact that especially poly(ADP-ribose) polymerase-1 is its own major target for modification, we could not detect this enzyme by mass spectrometry in these organelles. These data suggests a new way of targeted nuclear-mitochondrial signaling, mediated by nuclear poly (ADP-ribosyl)ation dependent on poly(ADP-ribose)polymerase-1.