Abstract
Non-thermal atmospheric pressure plasma (NTAPP) is an ionized gas at room temperature and has potential as a new apoptosis-promoting cancer therapy that acts by generating reactive oxygen species (ROS). However, it is imperative to determine its selectivity and standardize the components and composition of NTAPP. Here, we designed an NTAPP-generating apparatus combined with a He gas feeding system and demonstrated its high selectivity toward p53-mutated cancer cells. We first determined the proper conditions for NTAPP exposure to selectively induce apoptosis in cancer cells. The apoptotic effect of NTAPP was greater for p53-mutated cancer cells; artificial p53 expression in p53-negative HT29 cells decreased the pro-apoptotic effect of NTAPP. We also examined extra- and intracellular ROS levels in NTAPP-treated cells to deduce the mechanism of NTAPP action. While NTAPP-mediated increases in extracellular nitric oxide (NO) did not affect cell viability, intracellular ROS increased under NTAPP exposure and induced apoptotic cell death. This effect was dose-dependently reduced following treatment with ROS scavengers. NTAPP induced apoptosis even in doxorubicin-resistant cancer cell lines, demonstrating the feasibility of NTAPP as a potent cancer therapy. Collectively, these results strongly support the potential of NTAPP as a selective anticancer treatment, especially for p53-mutated cancer cells.
Highlights
Apoptosis is a well-known form of programmed cell death that removes damaged and unwanted cells; it serves as a crucial mechanism to defend tissues and organs from various types of stresses and cell damage [1]
The device is an annular type dielectric barrier discharge (DBD) [32] specified for Non-thermal atmospheric pressure plasma (NTAPP) generation under air or other gases when high-voltage sinusoidal wave forms or short duration pulses are applied between two electrodes, at least one of which is insulated
Because the exposure of NTAPP selectively induces apoptosis in HeLa cells but not in primary IMR90 or ASCs, we examined its effect on other types of cancer cells, including melanoma G361 and oral squamous carcinoma YD-9 cells, which are derived from cancers found in the surface of the body where plasma treatment could be readily applicable
Summary
Apoptosis is a well-known form of programmed cell death that removes damaged and unwanted cells; it serves as a crucial mechanism to defend tissues and organs from various types of stresses and cell damage [1]. When cells are subjected to various genotoxic and cellular stresses, such as oxidative stress, hypoxia, radiation, or chemotherapeutic drugs, p53 is activated, and its ubiquitin-dependent degradation is blocked, leading to an accumulation of active p53 transcription factor [1]. Activated p53 regulates cell cycle arrest, activation of anti-oxidants and DNA repair, and apoptosis by affecting the expression of its target genes, including the cyclin-dependent kinase (CDK) inhibitor p21/ WAF1 and genes involved in cell death, such as BAX, PUMA, NOXA, and Fas [2,3]. When cells are exposed to oxidative stress, p53 activates the transcription of sestrin, glutathione peroxidase (GPX), and aldehyde dehydrogenase (ALDH), playing a pivotal role in maintaining redox balance and genomic stability under oxidative stress [4,5]. Mutation of the p53 gene or disruption of pathways that lead to p53 activation have been frequently observed in most types of human cancer [6]
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