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Cold atmospheric plasma (CAP) has been used for the treatment of various cancers. The anti-cancer properties of CAP are mainly due to the reactive species generated from it. Here, we analyze the efficacy of CAP in combination with temozolomide (TMZ) in two different human glioblastoma cell lines, T98G and A172, in vitro using various conditions. We also establish an optimized dose of the co-treatment to study potential sensitization in TMZ-resistant cells. The removal of cell culture media after CAP treatment did not affect the sensitivity of CAP to cancer cells. However, keeping the CAP-treated media for a shorter time helped in the slight proliferation of T98G cells, while keeping the same media for longer durations resulted in a decrease in its survivability. This could be a potential reason for the sensitization of the cells in combination treatment. Co-treatment effectively increased the lactate dehydrogenase (LDH) activity, indicating cytotoxicity. Furthermore, apoptosis and caspase-3 activity also significantly increased in both cell lines, implying the anticancer nature of the combination. The microscopic analysis of the cells post-treatment indicated nuclear fragmentation, and caspase activity demonstrated apoptosis. Therefore, a combination treatment of CAP and TMZ may be a potent therapeutic modality to treat glioblastoma. This could also indicate that a pre-treatment with CAP causes the cells to be more sensitive to chemotherapy treatment. 

Cold atmospheric plasma (CAP) is an ionized gas, the product of a non-equilibrium discharge at atmospheric conditions. Both chemical and physical factors in CAP have been demonstrated to have unique biological impacts in cancer treatment. From a chemical-based perspective, the anti-cancer efficacy is determined by the cellular sensitivity to reactive species. CAP may also be used as a powerful anti-cancer modality based on its physical factors, mainly EM emission. Here, we delve into three CAP cancer treatment approaches, chemically based direct/indirect treatment and physical-based treatment by discussing their basic principles, features, advantages, and drawbacks. This review does not focus on the molecular mechanisms, which have been widely introduced in previous reviews. Based on these approaches and novel adaptive plasma concepts, we discuss the potential clinical application of CAP cancer treatment using a critical evaluation and forward-looking perspectives. 

Glioblastoma (GBM) is one of the most aggressive forms of adult brain cancers and is highly resistant to treatment, with a median survival of 12–18 months after diagnosis. The poor survival is due to its infiltrative pattern of invasion into the normal brain parenchyma, the diffuse nature of its growth, and its ability to quickly grow, spread, and relapse. Temozolomide is a well-known FDA-approved alkylating chemotherapy agent used for the treatment of high-grade malignant gliomas, and it has been shown to improve overall survival. However, in most cases, the tumor relapses. In recent years, CAP has been used as an emerging technology for cancer therapy. The purpose of this study was to implement a combination therapy of CAP and TMZ to enhance the effect of TMZ and apparently sensitize GBMs. In vitro evaluations in TMZ-sensitive and resistant GBM cell lines established a CAP chemotherapy enhancement and potential sensitization effect across various ranges of CAP jet application. This was further supported with in vivo findings demonstrating that a single CAP jet applied non-invasively through the skull potentially sensitizes GBM to subsequent treatment with TMZ. Gene functional enrichment analysis further demonstrated that co-treatment with CAP and TMZ resulted in a downregulation of cell cycle pathway genes. These observations indicate that CAP can be potentially useful in sensitizing GBM to chemotherapy and for the treatment of glioblastoma as a non-invasive translational therapy. 

Cold atmospheric plasma (CAP), an ionized gas with near room temperature, shows a wide application in medicine. CAP is a tunable source of complex chemical components including many reactive species, which allows CAP to exert many biological effects on bacterial, fungal, yeast, and mammalian cells particularly cancer cells. In this review, we discuss the novel state of the art CAP-based cancer treatment. We focus on the comparison between the direct CAP treatment and the indirect CAP treatment which implements the use of CAP-activated solutions. The difference between the two treatment strategies reveals two unique features of the biological response to CAP: the cell-based H 2 O 2 generation and the activation phenomenon. Short-lived reactive species and physical factors from plasma may trigger these two cellular responses. 

Abstract Cold atmospheric plasma (CAP) technology, a relatively novel technique mainly investigated as a stand-alone cancer treatment method in vivo and in vitro, is being proposed for application in conjunction with chemotherapy. In this study, we explore whether CAP, an ionized gas produced in laboratory settings and that operates at near room temperature, can enhance Temozolomide (TMZ) cytotoxicity on a glioblastoma cell line (U87MG). Temozolomide is the first line of treatment for glioblastoma, one of the most aggressive brain tumors that remains incurable despite advancements with treatment modalities. The cellular response to a single CAP treatment followed by three treatments with TMZ was monitored with a cell viability assay. According to the cell viability results, CAP treatment successfully augmented the effect of a cytotoxic TMZ dose (50 μM) and further restored the effect of a non-cytotoxic TMZ dose (10 μM). Application of CAP in conjunction TMZ increased DNA damage measured by the phosphorylation of H2AX and induced G2/M cell cycle arrest. These findings were supported by additional data indicating reduced cell migration and increased αvβ3 and αvβ5 cell surface integrin expression as a result of combined CAP–TMZ treatment. The data presented in this study serve as evidence that CAP technology can be a suitable candidate for combination therapy with existing chemotherapeutic drugs. CAP can also be investigated in future studies for sensitizing glioblastoma cells to TMZ and other drugs available in the market. 

Abstract Cold atmospheric plasma (CAP), a near room temperature ionized gas, has shown potential application in many branches of medicine, particularly in cancer treatment. In previous studies, the biological effect of CAP on cancer cells and other mammalian cells has been based solely on the chemical factors in CAP, particularly the reactive species. Therefore, plasma medicine has been regarded as a reactive species-based medicine, and the physical factors in CAP such as the thermal effect, ultraviolet irradiation, and electromagnetic effect have been regarded as ignorable factors. In this study, we investigated the effect of a physical CAP treatment on glioblastoma cells. For the first time, we demonstrated that the physical factors in CAP could reinstate the positive selectivity on CAP-treated astrocytes. The positive selectivity was a result of necrosis, a new cell death in glioblastoma cells characterized by the leak of bulk water from the cell membrane. The physically-based CAP treatment overcomed a large limitation of the traditional chemically based CAP treatment, which had complete dependence on the sensitivity of cells to reactive species. The physically-based CAP treatment is a potential non-invasive anti-tumor tool, which may have wide application for tumors located in deeper tissues.