Cold atmospheric plasma jet-generated RONS and their selective effects on normal and carcinoma cells (original) (raw)
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Synergistic Effect of H2O2 and NO2 in Cell Death Induced by Cold Atmospheric He Plasma
Scientific Reports, 2016
Cold atmospheric pressure plasmas (CAPPs) have emerged over the last decade as a new promising therapy to fight cancer. CAPPs' antitumor activity is primarily due to the delivery of reactive oxygen and nitrogen species (RONS), but the precise determination of the constituents linked to this anticancer process remains to be done. In the present study, using a micro-plasma jet produced in helium (He), we demonstrate that the concentration of H 2 O 2 , NO 2 − and NO 3 − can fully account for the majority of RONS produced in plasma-activated buffer. The role of these species on the viability of normal and tumour cell lines was investigated. Although the degree of sensitivity to H 2 O 2 is cell-type dependent, we show that H 2 O 2 alone cannot account for the toxicity of He plasma. Indeed, NO 2 − , but not NO 3 − , acts in synergy with H 2 O 2 to enhance cell death in normal and tumour cell lines to a level similar to that observed after plasma treatment. Our findings suggest that the efficiency of plasma treatment strongly depends on the combination of H 2 O 2 and NO 2 − in determined concentrations. We also show that the interaction of the He plasma jet with the ambient air is required to generate NO 2 − and NO 3 − in solution. Cancer is a leading cause of death worldwide and its incidence rate increases with the age of the population, the exposure to carcinogens and the modern lifestyle of the population. About two thirds of patients defeat their disease, and the combined action of surgery, radiotherapy and chemotherapy accounts for most cured cases 1. Alongside with these classical therapies, new therapies have emerged, such as anti-angiogenic therapy and immunotherapy 1. However, therapy resistance has been observed with every type of therapy that is available today, including poly-chemotherapy, radiotherapy, immunotherapy, and molecular targeted therapy 2. Importantly, sequencing of primary tumors has revealed that therapy-resistant clones already exist prior to targeted therapy, demonstrating that tumor heterogeneity in primary tumors confers a mechanism for inherent therapy resistance 2. Therefore, there is still the need of a new therapy that can overcome this problem. There are numerous publications showing that cold atmospheric pressure plasmas (CAPPs) are effective against tumour cells both in vitro and in vivo (ref. 3 and references therein). CAPPs are partially ionised gases containing a complex and reactive environment consisting of ions, electrons, free radicals, strong localised electric field, UV radiation, and neutral molecules. CAPPs' devices are classified in three categories: direct plasma sources that use the target as a counter electrode [e.g. floating electrode dielectric barrier discharge (FE-DBD)]; indirect plasma sources that do not use the target as a counter electrode (e.g. plasma jets); and hybrid plasma sources that combine the benefits of direct and indirect plasma sources 4-10. Different gases can be used to produce CAPPs such as Helium (He), Argon (Ar), Nitrogen (N 2), ambient air, or a mixture of gases 6,7. All the plasma sources developed for biomedical applications have in common that the major reactive molecules produced in CAPPs emerge when the components of the partially ionized gas (atoms, molecules, ions and electrons) interact with the molecules of the surrounding air, i.e. O 2 , N 2 and H 2 O, and with the biological sample which is usually a wet surface (e.g. cells in medium) 11-14. Consequently, the plasma composition and the subsequent effects on cells can vary enormously depending on the plasma source, the plasma settings, the ambient conditions and the biological target 12,15. Despite this large variability in the plasma composition, it is now widely accepted that the principal mode of plasma-cell interaction is the delivery of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that
Scientific reports, 2014
The atmospheric pressure helium plasma jet driven by pulsed dc voltage was utilized to treat human lung cancer cells in vitro. The properties of plasma plume were adjusted by the injection type and flow rate of additive oxygen gas in atmospheric pressure helium plasma jet. The plasma characteristics such as plume length, electric current and optical emission spectra (OES) were measured at different flow rates of additive oxygen to helium. The plasma plume length and total current decreased with an increase in the additive oxygen flow rate. The electron excitation temperature estimated by the Boltzmann plot from several excited helium emission lines increased slightly with the additive oxygen flow. The oxygen atom density in the gas phase estimated by actinometry utilizing argon was observed to increase with the additive oxygen flow. The concentration of intracellular reactive oxygen species (ROS) measured by fluorescence assay was found to be not exactly proportional to that of extr...
Plasma Medicine
Cold atmospheric pressure plasma (CAPP) has been proposed as a novel method for anticancer therapy. This field gained much interest in the last decade, with biological applications such as wound healing, bacterial sterilization, and cancer treatment. However, the mechanism at the basis of plasma-cell interaction remains unclear. Here, we studied the effect of helium (He) gas CAPP on oral squamous cell carcinoma (OSCC) in vitro. CAPP treatment was performed under different treatment time conditions: 1, 3, and 5 min. Results showed that CAPP treatment induces cell death in OSCC cells in a dose-dependent manner. He-CAPP also induces cell death and G1 cell cycle arrest associated with the ATM/P53 pathway. Furthermore, CAPP activates the mitochondria-mediated apoptosis pathway by enhancing Bax expression and of the Bcl-2 protein suppression. Hydrogen peroxide (H 2 O 2) generation increased immediately after He plasma treatment but reached basal level after 3 h. Further studies showed that CAPP increases intracellular ROS and RNS and reverts after a long period of plasma treatment. Taken together, these results indicated that He-CAPP induces cell death and cell cycle arrest and activates mitochondria-mediated apoptosis by increasing intracellular reactive oxygen and nitrogen species (ROS and RNS) in OSCC cells. Our study provides deep understanding of He-CAPP's effect on OSCC cells. We suggest that CAPP could be a potential therapeutic and clinical research tool for oral cancer treatment.
Applied Physics Letters, 2012
Helium/oxygen atmospheric pressure plasma jets driven by pulsed dc voltage with repetition rate of several tens of kilohertz are utilized for plasma-cell interactions. The effect of operating parameters on the apoptosis of cultured human bladder (EJ) cancer cells is investigated. The parameters such as applied voltage, pulse repetition frequency, and duty ratio determine the plasma dose. The apoptotic changes in cells with plasma treatment are detected by staining assay and flow cytometry. Apoptosis rates are observed to correlate well with both the plasma dose and the levels of intracellular and extracellular reactive oxygen species. V
PLoS ONE, 2014
The plasma jet has been proposed as a novel therapeutic method for cancer. Anticancer activity of plasma has been reported to involve mitochondrial dysfunction. However, what constituents generated by plasma is linked to this anticancer process and its mechanism of action remain unclear. Here, we report that the therapeutic effects of air plasma result from generation of reactive oxygen/nitrogen species (ROS/RNS) including H 2 O 2 , Ox, OH 2 , NO 2, NOx, leading to depolarization of mitochondrial membrane potential and mitochondrial ROS accumulation. Simultaneously, ROS/RNS activate c-Jun NH 2terminal kinase (JNK) and p38 kinase. As a consequence, treatment with air plasma jets induces apoptotic death in human cervical cancer HeLa cells. Pretreatment of the cells with antioxidants, JNK and p38 inhibitors, or JNK and p38 siRNA abrogates the depolarization of mitochondrial membrane potential and impairs the air plasma-induced apoptotic cell death, suggesting that the ROS/RNS generated by plasma trigger signaling pathways involving JNK and p38 and promote mitochondrial perturbation, leading to apoptosis. Therefore, administration of air plasma may be a feasible strategy to eliminate cancer cells.
AIP Advances, 2013
Atmospheric pressure plasma jets employing nitrogen, helium, or argon gases driven by low-frequency (several tens of kilohertz) ac voltage and pulsed dc voltage were fabricated and characterized. The changes in discharge current, optical emission intensities from reactive radicals, gas temperature, and plume length of plasma jets with the control parameters were measured and compared. The control parameters include applied voltage, working gas, and gas flow rate. As an application to plasma-cancer cell interactions, the effects of atmospheric pressure plasma jet on the morphology and intracellular reactive oxygen species (ROS) level of human lung adenocarcinoma cell (A549) and human bladder cancer cell (EJ) were explored. The experimental results show that the plasma can effectively control the intracellular concentrations of ROS. Although there exist slight differences in the production of ROS, helium, argon, or nitrogen plasma jets are found to be useful in enhancing the intracellular ROS concentrations in cancer cells.
Applied Physics Letters, 2013
The effects of atmospheric pressure plasma jet on cancer cells (human lung carcinoma cells) and normal cells (embryonic kidney cells and bronchial epithelial cells) were investigated. Using a detection dye, the production of intracellular reactive oxygen species (ROS) was found to be increased in plasma-treated cells compared to non-treated and gas flow-treated cells. A significant overproduction of ROS and a reduction in cell viability were induced by plasma exposure on cancer cells. Normal cells were observed to be less affected by the plasma-mediated ROS, and cell viability was less changed. The selective effect on cancer and normal cells provides a promising prospect of cold plasma as a cancer therapy. V
The effects of cold atmospheric plasma jets on B16 and COLO320 tumoral cells
Roumanian archives of microbiology and immunology
Cold atmospheric plasma treatment acts at the cellular level to remove diseased tissue without inflammation and damage, to suppress infections and to modulate the viability (apoptosis/necrosis) of tumoral cells. It is also known that, a major cause of anti-tumor chemotherapy failure is the development of multidrug resistance (MDR) of tumors. This study reveals the effect of high voltage pulsed, repetitive cold atmospheric plasma jets which are chemically activated with oxygen, on B16 tumoral cells (murine melanoma cell line) and COLO320DM multidrug resistant cells (human colon cancer cell line). The tests have been performed on human colon cancer cell line COLO320DM and murine melanoma cell line B16-F10. These cell lines have been treated with cold helium or helium-oxygen generated plasma jets and the consequent apoptosis has been analyzed by means of flow cytometric method. A treatment time-dependent apoptosis has been observed only in the case of 816-F10 cells interacting with hel...