Search Results
Physical plasma-treated saline promotes an immunogenic phenotype in CT26 colon cancer cells in vitro and in vivo
2019, Freund, Eric, Liedtke, Kim Rouven, van der Linde, Julia, Metelmann, Hans-Robert, Heidecke, Claus-Dieter, Partecke, Lars-Ivo, Bekeschus, Sander
Metastatic colorectal cancer is the fourth most common cause of cancer death. Current options in palliation such as hyperthermic intraperitoneal chemotherapy (HIPEC) present severe side effects. Recent research efforts suggested the therapeutic use of oxidant-enriched liquid using cold physical plasma. To investigate a clinically accepted treatment regimen, we assessed the antitumor capacity of plasma-treated saline solution. In response to such liquid, CT26 murine colon cancer cells were readily oxidized and showed cell growth with subsequent apoptosis, cell cycle arrest, and upregulation of immunogenic cell death (ICD) markers in vitro. This was accompanied by marked morphological changes with re-arrangement of actin fibers and reduced motility. Induction of an epithelial-to-mesenchymal transition phenotype was not observed. Key results were confirmed in MC38 colon and PDA6606 pancreatic cancer cells. Compared to plasma-treated saline, hydrogen peroxide was inferiorly toxic in 3D tumor spheroids but of similar efficacy in 2D models. In vivo, plasma-treated saline decreased tumor burden in Balb/C mice. This was concomitant with elevated numbers of intratumoral macrophages and increased T cell activation following incubation with CT26 cells ex vivo. Being a potential adjuvant for HIPEC therapy, our results suggest oxidizing saline solutions to inactivate colon cancer cells while potentially stimulating antitumor immune responses.
Cytochrome C oxidase Inhibition and Cold Plasma-derived Oxidants Synergize in Melanoma Cell Death Induction
2018-8-24, Gandhirajan, Rajesh Kumar, Rödder, Katrin, Bodnar, Yana, Pasqual-Melo, Gabriella, Emmert, Steffen, Griguer, Corinne E., Weltmann, Klaus-Dieter, Bekeschus, Sander
Despite striking advances in the treatment of metastasized melanoma, the disease is often still fatal. Attention is therefore paid towards combinational regimens. Oxidants endogenously produced in mitochondria are currently targeted in pre-clinical and clinical studies. Cytotoxic synergism of mitochondrial cytochrome c oxidase (CcO) inhibition in conjunction with addition of exogenous oxidants in 2D and 3D melanoma cell culture models were examined. Murine (B16) and human SK-MEL-28 melanoma cells exposed to low-dose CcO inhibitors (potassium cyanide or sodium azide) or exogenous oxidants alone were non-toxic. However, we identified a potent cytotoxic synergism upon CcO inhibition and plasma-derived oxidants that led to rapid onset of caspase-independent melanoma cell death. This was mediated by mitochondrial dysfunction induced by superoxide elevation and ATP depletion. This observation was validated by siRNA-mediated knockdown of COX4I1 in SK-MEL-28 cells with cytotoxicity in the presence of exogenous oxidants. Similar effects were obtained with ADDA 5, a recently identified specific inhibitor of CcO activity showing low toxicity in vivo. Human keratinocytes were not affected by this combinational treatment, suggesting selective effects on melanoma cells. Hence, targeting mitochondrial CcO activity in conjunction with exogenous pro oxidant therapies may constitute a new and effective melanoma treatment modality.