Abstract
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.
Highlights
Despite continuous advances in medicine, therapy and palliation of peritoneal colon cancer metastasis remains challenging[1]
Four regimens were used for treatment of CT26 colorectal cancer cells: P0, P20, P60, and H100 (100 μM of experimentally added H2O2 into 50 ml of phosphate-buffered saline (PBS) that corresponds to the concentration of H2O2 generated with the P60 condition)
To validate that this finding was related to oxidants deposited via plasma treatment and accumulating within cells, CT26 cells were labeled with chloromethyl 2′,7′-dichlorodihydrofluorescein diacetate (CM-H2DCF-DA), a redox-sensitive probe fluorescing upon intracellular oxidation[35] with help of intracellular oxidases (Fig. 1h)
Summary
Despite continuous advances in medicine, therapy and palliation of peritoneal colon cancer metastasis remains challenging[1]. One approach of cancer therapy is to utilize the immunogenic cancer cell death (ICD) triggering the immune system as defender against tumors In this concept, antigen-presenting cells phagocytosing tumor material become activated through sensing of tumor cell surface marker or the release of soluble factors that act as damage-associated molecular patterns (DAMPs)[30,31,32,33]. We here evaluated the potential of plasma-treated saline that may serve as basis for a future solution used for peritoneal lavage to induce toxicity and immunogenicity in colon cancer cells We found that such solution was storable over weeks, mediated cell death in tumor cells and altered their phenotype in disadvantage of metastatic spread, and acted as a bone fide inducer of pro-immunogenic markers
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