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Acidified Nitrite Contributes to the Antitumor Effect of Cold Atmospheric Plasma on Melanoma Cells.

ABSTRACT: Cold atmospheric plasma (CAP) is partially ionized gas near room temperature with previously reported antitumor effects. Despite extensive research and growing interest in this technology, active components and molecular mechanisms of CAP are not fully understood to date. We used Raman spectroscopy and colorimetric assays to determine elevated nitrite and nitrate levels after treatment with a MiniFlatPlaster CAP device. Previously, we demonstrated CAP-induced acidification. Cellular effects of nitrite and strong extracellular acidification were assessed using live-cell imaging of intracellular Ca²⁺ levels, cell viability analysis as well as quantification of p21 and DNA damage. We further characterized these observations by analyzing established molecular effects of CAP treatment. A synergistic effect of nitrite and acidification was found, leading to strong cytotoxicity in melanoma cells. Interestingly, protein nitration and membrane damage were absent after treatment with acidified nitrite, thereby challenging their contribution to CAP-induced cytotoxicity. Further, phosphorylation of ERK1/2 was increased after treatment with both acidified nitrite and indirect CAP. This study characterizes the impact of acidified nitrite on melanoma cells and supports the importance of RNS during CAP treatment. Further, it defines and evaluates important molecular mechanisms that are involved in the cancer cell response to CAP.

SUBMITTER: Zimmermann T

PROVIDER: S-EPMC8038463 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Combined Effect of Cold Atmospheric Plasma and Curcumin in Melanoma Cancer.

Project description:Curcumin (CUR) has interesting properties to cure cancer. Cold atmospheric plasma (CAP) is also an emerging biomedical technique that has great potential for cancer treatment. Therefore, the combined effect of CAP and CUR on inducing cytotoxicity and apoptosis of melanoma cancer cells might be promising. Here, we investigated the combined effects of CAP and CUR on cytotoxicity and apoptosis in B16-F10 melanoma cancer cells compared to L929 normal cells using MTT method, acridine orange/ethidium bromide fluorescence microscopic assay, and Annexin V/PI flow cytometry. In addition, the activation of apoptosis pathways was evaluated using BCL2, BAX, and Caspase-3 (CASP3) gene expression and ratio of BAX to BCL2 (BAX/BCL2). Finally, in silico study was performed to suggest the molecular mechanism of this combination therapy on melanoma cancer. Results showed that although combination therapy with CUR and CAP has cytotoxic and apoptotic effects on cancer cells, it did not improve apoptosis rate in melanoma B16-F10 cancer cells compared to monotherapy with CAP or CUR. In addition, evaluation of gene expression in cancer cell line confirmed that CUR and CAP concomitant treatment did not enhance the expression of apoptotic genes. In silico analysis of docked model suggested that CUR blocks aquaporin- (AQP-) 1 channel and prevents penetration of CAP-induced ROS into the cells. In conclusion, combination therapy with CAP and CUR does not improve the anticancer effect of each alone.

| S-EPMC8610675 | biostudies-literature

Synergistic effect of cold atmospheric pressure plasma and free or liposomal doxorubicin on melanoma cells.

Project description:The aim of the present study was to investigate combined effects of cold atmospheric plasma (CAP) and the chemotherapeutic drug doxorubicin (DOX) on murine and human melanoma cells, and normal cells. In addition to free drug, the combination of CAP with a liposomal drug (DOX-LIP) was also studied for the first time. Thiazolyl blue tetrazolium bromide (MTT) and Trypan Blue exclusion assays were used to evaluate cell viability; the mechanism of cell death was evaluated by flow cytometry. Combined treatment effects on the clonogenic capability of melanoma cells, was also tested with soft agar colony formation assay. Furthermore the effect of CAP on the cellular uptake of DOX or DOX-LIP was examined. Results showed a strong synergistic effect of CAP and DOX or DOX-LIP on selectively decreasing cell viability of melanoma cells. CAP accelerated the apoptotic effect of DOX (or DOX-LIP) and dramatically reduced the aggressiveness of melanoma cells, as the combination treatment significantly decreased their anchorage independent growth. Moreover, CAP did not result in increased cellular uptake of DOX under the present experimental conditions. In conclusion, CAP facilitates DOX cytotoxic effects on melanoma cells, and affects their metastatic potential by reducing their clonogenicity, as shown for the first time.

| S-EPMC8292331 | biostudies-literature

Cold Atmospheric Plasma and Silymarin Nanoemulsion Activate Autophagy in Human Melanoma Cells.

Project description:Autophagy is reported as a survival or death-promoting pathway that is highly debatable in different kinds of cancer. Here, we examined the co-effect of cold atmospheric plasma (CAP) and silymarin nanoemulsion (SN) treatment on G-361 human melanoma cells via autophagy induction. The temperature and pH of the media, along with the cell number, were evaluated. The intracellular glucose level and PI3K/mTOR and EGFR downstream pathways were assessed. Autophagy-related genes, related transcriptional factors, and autophagy induction were estimated using confocal microscopy, flow cytometry, and ELISA. CAP treatment increased the temperature and pH of the media, while its combination with SN resulted in a decrease in intracellular ATP with the downregulation of PI3K/AKT/mTOR survival and RAS/MEK transcriptional pathways. Co-treatment blocked downstream paths of survival pathways and reduced PI3K (2 times), mTOR (10 times), EGFR (5 times), HRAS (5 times), and MEK (10 times). CAP and SN co-treated treatment modulates transcriptional factor expressions (ZKSCAN3, TFEB, FOXO1, CRTC2, and CREBBP) and specific genes (BECN-1, AMBRA-1, MAP1LC3A, and SQSTM) related to autophagy induction. CAP and SN together activate autophagy in G-361 cells by activating PI3K/mTOR and EGFR pathways, expressing autophagy-related transcription factors and genes.

| S-EPMC7139470 | biostudies-literature

Cold Atmospheric Plasma Triggers Apoptosis via the Unfolded Protein Response in Melanoma Cells.

Project description:Cold atmospheric plasma (CAP) describes a partially ionized gas carrying large amounts of reactive oxygen (ROS) and nitrogen species (RNS). Numerous studies reported strong antitumor activity of CAP, thus rendering it a promising approach for tumor therapy. Although several cellular mechanisms of its cytotoxicity were identified in recent years, the exact molecular effects and contributing signaling pathways are yet to be discovered. We discovered a strong activation of unfolded protein response (UPR) after CAP treatment with increased C/EBP homologous protein (CHOP) expression, which was mainly caused by protein misfolding and calcium loss in the endoplasmic reticulum. In addition, both ceramide level and ceramide metabolism were reduced after CAP treatment, which was then linked to the UPR activation. Pharmacological inhibition of ceramide metabolism resulted in sensitization of melanoma cells for CAP both in vitro and ex vivo. This study identified a novel mechanism of CAP-induced apoptosis in melanoma cells and thereby contributes to its potential application in tumor therapy.

| S-EPMC9954601 | biostudies-literature

Acidification is an Essential Process of Cold Atmospheric Plasma and Promotes the Anti-Cancer Effect on Malignant Melanoma Cells.

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| S-EPMC6562457 | biostudies-literature

Cold Atmospheric Plasma Changes the Amino Acid Composition of Solutions and Influences the Anti-Tumor Effect on Melanoma Cells.

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| S-EPMC8346059 | biostudies-literature

Cold atmospheric plasma causes a calcium influx in melanoma cells triggering CAP-induced senescence.

Project description:Cold atmospheric plasma (CAP) is a promising approach in anti-cancer therapy, eliminating cancer cells with high selectivity. However, the molecular mechanisms of CAP action are poorly understood. In this study, we investigated CAP effects on calcium homeostasis in melanoma cells. We observed increased cytoplasmic calcium after CAP treatment, which also occurred in the absence of extracellular calcium, indicating the majority of the calcium increase originates from intracellular stores. Application of previously CAP-exposed extracellular solutions also induced cytoplasmic calcium elevations. A substantial fraction of this effect remained when the application was delayed for one hour, indicating the chemical stability of the activating agent(s). Addition of ryanodine and cyclosporin A indicate the involvement of the endoplasmatic reticulum and the mitochondria. Inhibition of the cytoplasmic calcium elevation by the intracellular chelator BAPTA blocked CAP-induced senescence. This finding helps to understand the molecular influence and the mode of action of CAP on tumor cells.

| S-EPMC6030087 | biostudies-literature

Effect of cold atmospheric plasma (CAP) in MCF-7

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-01-24 | GSE131480 | GEO

Effect of cold atmospheric plasma treatment on the metabolites of human leukemia cells.

Project description:BackgroundAcute myeloid leukemia (AML) is a typically fatal malignancy and new drug and treatment need to be developed for a better survival outcome. Cold atmospheric plasma (CAP) is a novel technology, which has been widely applied in biomedicine, especially in various of cancer treatment. However, the changes in cell metabolism after CAP treatment of leukemia cells have been rarely studied.MethodsIn this study, we investigated the metabolite profiling of plasma treatment on leukemia cells based on Gas Chromatography Tandem Time-of-Flight Mass Spectrometry (GC-TOFMS). Simultaneously, we conducted a series of bioinformatics analysis of metabolites and metabolic pathways with significant differences after basic data analysis.Results800 signals were detected by GC-TOF mass-spectrometry and then evaluated using PCA and OPLS-DA. All the differential metabolites were listed and the related metabolic pathways were analyzed by KEGG pathway. The results showed that alanine, aspartate and glutamate metabolism had a significant change after plasma treatment. Meanwhile, d-glutamine and d-glutamate metabolism were significantly changed by CAP. Glutaminase activity was decreased after plasma treatment, which might lead to glutamine accumulation and leukemia cells death.ConclusionsWe found the above two metabolic pathways vulnerable to plasma treatment, which might result in leukemia cells death and might be the cornerstone of further exploration of plasma treatment targets.

| S-EPMC6525389 | biostudies-literature

Comparison of Direct and Indirect cold atmospheric-pressure plasma methods in the B16F10 melanoma cancer cells treatment.

Project description:In this study a novel method was implemented and investigated in order to destroy cancer cells inside the mouse body on a clinical level. In the case of in-vitro study, MTT assay was employed to discover an effective dose of applied plasma and distinguish the plasma effect in direct and in indirect treatments. Tumor growth was also measured in in-vivo section so that the effectiveness of direct and indirect treatments could be compared. Furthermore, an investigation was conducted to study the interferences between a conventional method (chemotherapy) and plasma treatment so as to increase the effectiveness of treatment inside the body. Hematoxylin and Eosin, Flow Cytometry, TUNEL and Western Blot assay were used to investigate any cell alteration and the impact of various treatment methods on cancer cell and amount of their apoptosis and protein levels. Radiology and CT scan images were taken to determine the final tumor volume. The results showed a significant cell death and substantial reduction in tumor growth in direct plasma treatment in comparison with indirect plasma treatment. Eventually, dramatic destruction of cancer cells was observed while using of indirect plasma-chemotherapy combination, thus introducing an effective method for deep tissue tumors can be introduced.

| S-EPMC5955918 | biostudies-literature

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