The Strong Cell-based Hydrogen Peroxide Generation Triggered by Cold Atmospheric Plasma

📝 Abstract

Hydrogen peroxide (H2O2) is an important signaling molecule in cancer cells. However, the significant secretion of H2O2 by cancer cells have been rarely observed. Cold atmospheric plasma (CAP) is a near room temperature ionized gas composed of neutral particles, charged particles, reactive species, and electrons. Here, we first demonstrated that breast cancer cells and pancreatic adenocarcinoma cells generated micromolar level H2O2 during just 1 min of direct CAP treatment on these cells. The cell-based H2O2 generation is affected by the medium volume, the cell confluence, as well as the discharge voltage. The application of cold atmospheric plasma (CAP) in the cancer treatment has been intensively investigated over the past decade. Several cellular responses to the CAP treatment have been observed including the consumption of the CAP-originated reactive species, the rise of intracellular reactive oxygen species, the damage on DNA and mitochondria, as well as the activation of apoptotic events. This is a new previously unknown cellular response to CAP, which provides a new prospective to understand the interaction between CAP and cells.

💡 Analysis

Hydrogen peroxide (H2O2) is an important signaling molecule in cancer cells. However, the significant secretion of H2O2 by cancer cells have been rarely observed. Cold atmospheric plasma (CAP) is a near room temperature ionized gas composed of neutral particles, charged particles, reactive species, and electrons. Here, we first demonstrated that breast cancer cells and pancreatic adenocarcinoma cells generated micromolar level H2O2 during just 1 min of direct CAP treatment on these cells. The cell-based H2O2 generation is affected by the medium volume, the cell confluence, as well as the discharge voltage. The application of cold atmospheric plasma (CAP) in the cancer treatment has been intensively investigated over the past decade. Several cellular responses to the CAP treatment have been observed including the consumption of the CAP-originated reactive species, the rise of intracellular reactive oxygen species, the damage on DNA and mitochondria, as well as the activation of apoptotic events. This is a new previously unknown cellular response to CAP, which provides a new prospective to understand the interaction between CAP and cells.

📄 Content

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The Strong Cell-based Hydrogen Peroxide Generation Triggered by Cold Atmospheric Plasma

Dayun Yan1*, Haitao Cui1, Wei Zhu1, Annie Talbot2, Lijie Grace Zhang1, Jonathan H. Sherman3, and Michael Keidar1*

1Department of Mechanical and Aerospace Engineering, The George Washington University, Science & Engineering Hall, 800 22nd Street, NW, Washington, DC 20052, USA
2Columbian College of Arts and Sciences, The George Washington University, Philips Hall, 801 22nd Street, NW, Suite 212, Washington, DC 20052, USA 3Neurological Surgery, The George Washington University, Foggy Bottom South Pavilion, 22nd Street, NW, 7th Floor, Washington, DC 20037, USA *Corresponding authors: Dayun Yan ydy2012@gwmail.gwu.edu, Michael Keidar keidar@gwu.edu

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Abstract. Hydrogen peroxide (H2O2) is an important signaling molecule in cancer cells. However, the significant secretion of H2O2 by cancer cells have been rarely observed. Cold atmospheric plasma (CAP) is a near room temperature ionized gas composed of neutral particles, charged particles, reactive species, and electrons. Here, we first demonstrated that breast cancer cells and pancreatic adenocarcinoma cells generated micromolar level H2O2 during just 1 min of direct CAP treatment on these cells. The cell-based H2O2 generation is affected by the medium volume, the cell confluence, as well as the discharge voltage. The application of cold atmospheric plasma (CAP) in the cancer treatment has been intensively investigated over the past decade. Several cellular responses to the CAP treatment have been observed including the consumption of the CAP-originated reactive species, the rise of intracellular reactive oxygen species, the damage on DNA and mitochondria, as well as the activation of apoptotic events. This is a new previously unknown cellular response to CAP, which provides a new prospective to understand the interaction between CAP and cells.

Keywords. Cold atmospheric plasma; cancer cells; cell-based H2O2 generation; plasma medicine.

Introduction.
H2O2 is an important signaling molecule in cancer cells (1). The production of nanomolar (nM) level of H2O2 by several cancer cell lines including melanomas, neuroblastoma, colon carcinoma, and ovarian carcinoma have been observed two decades ago (2). H2O2 may increase the genetic instability of cancer cells by inducing DNA strand breaks, damage on guanine or thymine bases, and the sister chromatid exchanges, which may facilitate the malignant process of cancer cells, 3

such as proliferation, apoptosis resistance, metastasis, angiogenesis and hypoxia-inducible factor 1 activation (1, 2). On the other hand, H2O2 alone with a relative high concentration or as the mediator of a series of anticancer drugs can selectively induce apoptosis in cancer cells (1, 3–5). H2O2 may have promising application in cancer treatment at least as a mediator of series of physical or chemical strategies.

Cold atmospheric plasma (CAP), a near room temperature ionized gas composed of charged particles, neutral particles and electrons, has shown its promising application in cancer treatment over the past decade (6–11). CAP not only effectively decreases the growth of many cancer cell lines in vitro through reactive species-triggered cell death but also significantly inhibits or halts the growth of subcutaneous xenograft tumors or melanoma in mice by the direct CAP treatment just above the skin (8, 14–17). The reactive oxygen species (ROS) and the reactive nitrogen species (RNS) have been regarded as the main factors contributing to the complicate interaction between CAP and cancer cells in vitro and in vivo (12, 13). Many studies conclude that the death of the CAP-treated cancer cells in vitro is due to the apoptosis triggered by the significant rise of intracellular ROS, DNA damage, as well as mitochondrial damage (7, 11, 18–21).

Among dozens of CAP-originated species in aqueous solutions, H2O2 has been proven to be a main factor triggering the death of cancer cells in vitro (22–26). H2O2 has not been detected in the emission spectra of CAP in the gas phase (19). The H2O2 in aqueous solution is due to the recombination reactions between short-life species OH. (27, 28). To date, CAP is the only confirmed extracellular H2O2 source in plasma medicine. Cells have just been regarded as a consumer for the H2O2 generated by CAP (11, 24). However, using a solution with H2O2 alone 4

does not cause the same decrease in cancer cells viability as seen following the CAP treatment (29, 30). Thus, the CAP treatment on cancer cells cannot be simply regarded as a H2O2-treatment.

In addition to the direct CAP treatment, another strategy using the CAP-stimulated solutions (PSS) to inhibit the growth of cancer cells in vitro or to inhibit the growth of tumorous tissues in mice through injection has been also demonstrated recently (31–34). PSS is also named as the indirect CAP

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