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Cancers
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Advances in Plasma Oncology toward Clinical Translation
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Advances in Plasma Oncology toward Clinical Translation

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 January 2021) | Viewed by 60035

Special Issue Editors

Prof. Dr. Annemie Bogaerts

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Guest Editor
Department of Chemistry, University of Antwerp, Campus Drie Eiken – Room B2.09, Universiteitsplein 1, Wilrijk, BE-2610 Antwerp, Belgium
Interests: plasma and plasma–surface interactions by means of computer modeling and experiments, for various applications, with a major focus on green chemistry; plasma catalysis
Special Issues, Collections and Topics in MDPI journals
Dr. Katharina Stapelmann

E-Mail Website
Guest Editor
Department of Nuclear Engineering, NorthCarolina State University, Raleigh, North Carolina, USA
Interests: plasma diagnostics; plasma chemistry; plasma–liquid interaction, plasma–cell interaction; plasma for life science applications; plasma cancer treatment
Dr. Abraham Lin

E-Mail Website
Guest Editor
Department of Chemistry, Antwarp University, Antwerpen, Belgium
Interests: plasma medicine; cancer biology; immune-modulation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the past decade, cold atmospheric plasmas (CAPs) have been under investigation for their potential for cancer treatment, thus opening the young, multidisciplinary field of plasma oncology. CAPs are tunable sources for the production and delivery of reactive oxygen and nitrogen species (RONS), which positions them as a unique tool to study intracellular redox pathways and for development as a novel redox therapy.

As new research tools and more sophisticated 3D in vitro cancer models are emerging, the role of the tumor microenvironment is attracting greater attention among plasma-cancer researchers. Strategies for combination therapy, e.g., immunotherapy, are also of great importance and are currently under development. There is a clear need for a better understanding of the underlying mechanisms, but at the same time, we should start thinking about the move toward clinical translation of this promising technology.

In this Special Issue, we will publish original research papers that provide fundamental understanding into the mechanisms of CAPs in cancer treatment, ranging from computer modeling to in vitro and in vivo experiments and clinical trials. New insights should preferably be considered and discussed in the context of clinical translation or application.

Dr. Annemie Bogaerts
Dr. Katharina Stapelmann
Dr. Abraham Lin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Mechanistic studies of plasma effects on cancer cells;
  • Strategies for combination therapy;
  • Cancer-immunity cycle;
  • Tumor microenvironment;
  • Redox therapy with plasma;
  • 3D in vitro cancer models;
  • In vivo studies;
  • Safety analysis.

Published Papers (17 papers)

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Editorial

Jump to: Research, Review

2 pages, 158 KiB  
Editorial
Advances in Plasma Oncology toward Clinical Translation
by Abraham Lin, Katharina Stapelmann and Annemie Bogaerts
Cancers 2020, 12(11), 3283; https://doi.org/10.3390/cancers12113283 - 06 Nov 2020
Cited by 3 | Viewed by 1504
Abstract
This Special Issue on “Advances in Plasma Oncology Toward Clinical Translation” aims to bring together cutting-edge research papers within the field in the context of clinical translation and application [...] Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)

Research

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25 pages, 22548 KiB  
Article
In Vitro and In Vivo Enhancement of Temozolomide Effect in Human Glioblastoma by Non-Invasive Application of Cold Atmospheric Plasma
by Vikas Soni, Manish Adhikari, Hayk Simonyan, Li Lin, Jonathan H. Sherman, Colin N. Young and Michael Keidar
Cancers 2021, 13(17), 4485; https://doi.org/10.3390/cancers13174485 - 06 Sep 2021
Cited by 26 | Viewed by 5280
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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22 pages, 4578 KiB  
Article
Epithelial-to-Mesenchymal Transition Enhances Cancer Cell Sensitivity to Cytotoxic Effects of Cold Atmospheric Plasmas in Breast and Bladder Cancer Systems
by Peiyu Wang, Renwu Zhou, Patrick Thomas, Liqian Zhao, Rusen Zhou, Susmita Mandal, Mohit Kumar Jolly, Derek J. Richard, Bernd H. A. Rehm, Kostya (Ken) Ostrikov, Xiaofeng Dai, Elizabeth D. Williams and Erik W. Thompson
Cancers 2021, 13(12), 2889; https://doi.org/10.3390/cancers13122889 - 09 Jun 2021
Cited by 33 | Viewed by 3465
Abstract
Cold atmospheric plasma (CAP) has emerged as a highly selective anticancer agent, most recently in the form of plasma-activated medium (PAM). Since epithelial–mesenchymal transition (EMT) has been implicated in resistance to various cancer therapies, we assessed whether EMT status is associated with PAM [...] Read more.
Cold atmospheric plasma (CAP) has emerged as a highly selective anticancer agent, most recently in the form of plasma-activated medium (PAM). Since epithelial–mesenchymal transition (EMT) has been implicated in resistance to various cancer therapies, we assessed whether EMT status is associated with PAM response. Mesenchymal breast cancer cell lines, as well as the mesenchymal variant in an isogenic EMT/MET human breast cancer cell system (PMC42-ET/LA), were more sensitive to PAM treatment than their epithelial counterparts, contrary to their responses to other therapies. The same trend was seen in luminal muscle-invasive bladder cancer model (TSU-Pr1/B1/B2) and the non-muscle-invasive basal 5637 bladder cancer cell line. Three-dimensional spheroid cultures of the bladder cancer cell lines were less sensitive to the PAM treatment compared to their two-dimensional counterparts; however, incrementally better responses were again seen in more mesenchymally-shifted cell lines. This study provides evidence that PAM preferentially inhibits mesenchymally-shifted carcinoma cells, which have been associated with resistance to other therapies. Thus, PAM may represent a novel treatment that can selectively inhibit triple-negative breast cancers and a subset of aggressive bladder cancers, which tend to be more mesenchymal. Our approach may potentially be utilized for other aggressive cancers exhibiting EMT and opens new opportunities for CAP and PAM as a promising new onco-therapy. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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19 pages, 3090 KiB  
Article
Differential Effect of Non-Thermal Plasma RONS on Two Human Leukemic Cell Populations
by Hager Mohamed, Eric Gebski, Rufranshell Reyes, Samuel Beane, Brian Wigdahl, Fred C. Krebs, Katharina Stapelmann and Vandana Miller
Cancers 2021, 13(10), 2437; https://doi.org/10.3390/cancers13102437 - 18 May 2021
Cited by 9 | Viewed by 2477
Abstract
Non-thermal plasma application to cancer cells is known to induce oxidative stress, cytotoxicity and indirect immunostimulatory effects on antigen presenting cells (APCs). The purpose of this study was to evaluate the responses of two leukemic cell lines—Jurkat T lymphocytes and THP-1 monocytes—to NTP-generated [...] Read more.
Non-thermal plasma application to cancer cells is known to induce oxidative stress, cytotoxicity and indirect immunostimulatory effects on antigen presenting cells (APCs). The purpose of this study was to evaluate the responses of two leukemic cell lines—Jurkat T lymphocytes and THP-1 monocytes—to NTP-generated reactive oxygen and nitrogen species (RONS). Both cell types depleted hydrogen peroxide, but THP-1 cells neutralized it almost immediately. Jurkat cells transiently blunted the frequency-dependent increase in nitrite concentrations in contrast to THP-1 cells, which exhibited no immediate effect. A direct relationship between frequency-dependent cytotoxicity and mitochondrial superoxide was observed only in Jurkat cells. Jurkat cells were very responsive to NTP in their display of calreticulin and heat shock proteins 70 and 90. In contrast, THP-1 cells were minimally responsive or unresponsive. Despite no NTP-dependent decrease in cell surface display of CD47 in either cell line, both cell types induced migration of and phagocytosis by APCs. Our results demonstrate that cells modulate the RONS-mediated changes in liquid chemistry, and, importantly, the resultant immunomodulatory effects of NTP can be independent of NTP-induced cytotoxicity. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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20 pages, 14012 KiB  
Article
Cold Atmospheric Plasma Increases Temozolomide Sensitivity of Three-Dimensional Glioblastoma Spheroids via Oxidative Stress-Mediated DNA Damage
by Priyanka Shaw, Naresh Kumar, Angela Privat-Maldonado, Evelien Smits and Annemie Bogaerts
Cancers 2021, 13(8), 1780; https://doi.org/10.3390/cancers13081780 - 08 Apr 2021
Cited by 25 | Viewed by 3703
Abstract
Glioblastoma multiforme (GBM) is the most frequent and aggressive primary malignant brain tumor in adults. Current standard radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide (TMZ) yield poor clinical outcome. This is due to the stem-like properties of tumor cells and genetic [...] Read more.
Glioblastoma multiforme (GBM) is the most frequent and aggressive primary malignant brain tumor in adults. Current standard radiotherapy and adjuvant chemotherapy with the alkylating agent temozolomide (TMZ) yield poor clinical outcome. This is due to the stem-like properties of tumor cells and genetic abnormalities in GBM, which contribute to resistance to TMZ and progression. In this study, we used cold atmospheric plasma (CAP) to enhance the sensitivity to TMZ through inhibition of antioxidant signaling (linked to TMZ resistance). We demonstrate that CAP indeed enhances the cytotoxicity of TMZ by targeting the antioxidant specific glutathione (GSH)/glutathione peroxidase 4 (GPX4) signaling. We optimized the threshold concentration of TMZ on five different GBM cell lines (U251, LN18, LN229, U87-MG and T98G). We combined TMZ with CAP and tested it on both TMZ-sensitive (U251, LN18 and LN229) and TMZ-resistant (U87-MG and T98G) cell lines using two-dimensional cell cultures. Subsequently, we used a three-dimensional spheroid model for the U251 (TMZ-sensitive) and U87-MG and T98G (TMZ-resistant) cells. The sensitivity of TMZ was enhanced, i.e., higher cytotoxicity and spheroid shrinkage was obtained when TMZ and CAP were administered together. We attribute the anticancer properties to the release of intracellular reactive oxygen species, through inhibiting the GSH/GPX4 antioxidant machinery, which can lead to DNA damage. Overall, our findings suggest that the combination of CAP with TMZ is a promising combination therapy to enhance the efficacy of TMZ towards the treatment of GBM spheroids. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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23 pages, 3196 KiB  
Article
Plasma-Activated Medium Potentiates the Immunogenicity of Tumor Cell Lysates for Dendritic Cell-Based Cancer Vaccines
by Sergej Tomić, Anđelija Petrović, Nevena Puač, Nikola Škoro, Marina Bekić, Zoran Lj. Petrović and Miodrag Čolić
Cancers 2021, 13(7), 1626; https://doi.org/10.3390/cancers13071626 - 01 Apr 2021
Cited by 26 | Viewed by 4060
Abstract
Autologous dendritic cells (DCs)-based vaccines are considered quite promising for cancer immunotherapy due to their exquisite potential to induce tumor antigen-specific cytotoxic T cells. However, a lack of efficient protocols for inducing immunogenic tumor antigens limits the efficacy of DC-based cancer vaccines. Here, [...] Read more.
Autologous dendritic cells (DCs)-based vaccines are considered quite promising for cancer immunotherapy due to their exquisite potential to induce tumor antigen-specific cytotoxic T cells. However, a lack of efficient protocols for inducing immunogenic tumor antigens limits the efficacy of DC-based cancer vaccines. Here, we found that a plasma-activated medium (PAM) induces immunogenic cell death (ICD) in tumor cells but not in an immortalized L929 cell line or human peripheral blood mononuclear cells. PAM induced an accumulation of reactive oxygen species (ROS), autophagy, apoptosis, and necrosis in a concentration-dependent manner. The tumor lysates prepared after PAM treatment displayed increased immunogenicity in a model of human monocyte-derived DCs, compared to the lysates prepared by a standard freezing/thawing method. Mature DCs loaded with PAM lysates showed an increased maturation potential, as estimated by their increased expression of CD83, CD86, CD40, IL-12/IL-10 production, and attenuated PDL1 and ILT-4 expression, compared to the DCs treated with control tumor lysates. Moreover, in co-culture with allogeneic T cells, DCs loaded with PAM-lysates increased the proportion of cytotoxic IFN-γ+ granzyme A+ CD8+ T cells and IL-17A-producing T cells and preserved the Th1 response. In contrast, control tumor lysates-treated DCs increased the frequency of Th2 (CD4+IL-4+), CD4, and CD8 regulatory T cell subtypes, none of which was observed with DCs loaded with PAM-lysates. Cumulatively, these results suggest that the novel method for preparing immunogenic tumor lysates with PAM could be suitable for improved DC-based immunotherapy of cancer patients. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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15 pages, 2356 KiB  
Article
Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy
by Kae Nakamura, Nobuhisa Yoshikawa, Yuko Mizuno, Miwa Ito, Hiromasa Tanaka, Masaaki Mizuno, Shinya Toyokuni, Masaru Hori, Fumitaka Kikkawa and Hiroaki Kajiyama
Cancers 2021, 13(5), 1141; https://doi.org/10.3390/cancers13051141 - 07 Mar 2021
Cited by 23 | Viewed by 2457
Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC’s lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in [...] Read more.
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC’s lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in vitro and in vivo. Here we investigated how PAM inhibits intraperitoneal metastasis. We studied PAM’s inhibition of micro-dissemination onto the omentum by performing in vivo imaging in combination with a sequential histological analysis. The results revealed that PAM induced macrophage infiltration into the disseminated lesion. The iNOS-positive signal was co-localized at the macrophages in the existing lesion, indicating that PAM might induce M1-type macrophages. This may be another mechanism of the antitumor effect through a PAM-evoked immune response. Intraperitoneal lavage with plasma-activated lactate Ringer’s solution (PAL) significantly improved the overall survival rate in an ovarian cancer mouse model. Our results demonstrated the efficiency and practicality of aqueous plasma for clinical applications. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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30 pages, 7413 KiB  
Article
Role of Short- and Long-Lived Reactive Species on the Selectivity and Anti-Cancer Action of Plasma Treatment In Vitro
by Kyriakos Sklias, João Santos Sousa and Pierre-Marie Girard
Cancers 2021, 13(4), 615; https://doi.org/10.3390/cancers13040615 - 04 Feb 2021
Cited by 33 | Viewed by 3060
Abstract
(1) Plasma-activated liquids (PAL) have been extensively studied for their anti-cancer properties. Two treatment modalities can be applied to the cells, direct and indirect plasma treatments, which differ by the environment to which the cells are exposed. For direct plasma treatment, the cells [...] Read more.
(1) Plasma-activated liquids (PAL) have been extensively studied for their anti-cancer properties. Two treatment modalities can be applied to the cells, direct and indirect plasma treatments, which differ by the environment to which the cells are exposed. For direct plasma treatment, the cells covered by a liquid are present during the plasma treatment time (phase I, plasma ON) and the incubation time (phase II, plasma OFF), while for indirect plasma treatment, phase I is cell-free and cells are only exposed to PAL during phase II. The scope of this work was to study these two treatment modalities to bring new insights into the potential use of PAL for cancer treatment. (2) We used two models of head and neck cancer cells, CAL27 and FaDu, and three models of normal cells (1Br3, NHK, and RPE-hTERT). PBS was used as the liquid of interest, and the concentration of plasma-induced H2O2, NO2− and NO3−, as well as pH change, were measured. Cells were exposed to direct plasma treatment, indirect plasma treatment or reconstituted buffer (PBS adjusted with plasma-induced concentrations of H2O2, NO2−, NO3− and pH). Metabolic cell activity, cell viability, lipid peroxidation, intracellular ROS production and caspase 3/7 induction were quantified. (3) If we showed that direct plasma treatment is slightly more efficient than indirect plasma treatment and reconstituted buffer at inducing lipid peroxidation, intracellular increase of ROS and cancer cell death in tumor cells, our data also revealed that reconstituted buffer is equivalent to indirect plasma treatment. In contrast, normal cells are quite insensitive to these two last treatment modalities. However, they are extremely sensitive to direct plasma treatment. Indeed, we found that phase I and phase II act in synergy to trigger cell death in normal cells and are additive concerning tumor cell death. Our data also highlight the presence in plasma-treated PBS of yet unidentified short-lived reactive species that contribute to cell death. (4) In this study, we provide strong evidence that, in vitro, the concentration of RONS (H2O2, NO2− and NO3−) in combination with the acidic pH are the main drivers of plasma-induced PBS toxicity in tumor cells but not in normal cells, which makes ad hoc reconstituted solutions powerful anti-tumor treatments. In marked contrast, direct plasma treatment is deleterious for normal cells in vitro and should be avoided. Based on our results, we discuss the limitations to the use of PAL for cancer treatments. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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15 pages, 3499 KiB  
Article
Oxidation of Innate Immune Checkpoint CD47 on Cancer Cells with Non-Thermal Plasma
by Abraham Lin, Jamoliddin Razzokov, Hanne Verswyvel, Angela Privat-Maldonado, Joey De Backer, Maksudbek Yusupov, Edgar Cardenas De La Hoz, Peter Ponsaerts, Evelien Smits and Annemie Bogaerts
Cancers 2021, 13(3), 579; https://doi.org/10.3390/cancers13030579 - 02 Feb 2021
Cited by 26 | Viewed by 3548
Abstract
Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that [...] Read more.
Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that are overexpressed on cancerous cells. Here, 3D in vitro tumor models, an in vivo mouse model, and molecular dynamics simulations are used to investigate the effect of NTP on CD47, a key innate immune checkpoint. CD47 is immediately modulated after NTP treatment and simulations reveal the potential oxidized salt-bridges responsible for conformational changes. Umbrella sampling simulations of CD47 with its receptor, signal-regulatory protein alpha (SIRPα), demonstrate that the induced-conformational changes reduce its binding affinity. Taken together, this work provides new insight into fundamental, chemical NTP-cancer cell interaction mechanisms and a previously overlooked advantage of present NTP cancer therapy: reducing immunosuppressive signals on the surface of cancer cells. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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17 pages, 4421 KiB  
Article
Physical Plasma-Treated Skin Cancer Cells Amplify Tumor Cytotoxicity of Human Natural Killer (NK) Cells
by Ramona Clemen, Pepijn Heirman, Abraham Lin, Annemie Bogaerts and Sander Bekeschus
Cancers 2020, 12(12), 3575; https://doi.org/10.3390/cancers12123575 - 30 Nov 2020
Cited by 24 | Viewed by 2869
Abstract
Skin cancers have the highest prevalence of all human cancers, with the most lethal forms being squamous cell carcinoma and malignant melanoma. Besides the conventional local treatment approaches like surgery and radiotherapy, cold physical plasmas are emerging anticancer tools. Plasma technology is used [...] Read more.
Skin cancers have the highest prevalence of all human cancers, with the most lethal forms being squamous cell carcinoma and malignant melanoma. Besides the conventional local treatment approaches like surgery and radiotherapy, cold physical plasmas are emerging anticancer tools. Plasma technology is used as a therapeutic agent by generating reactive oxygen species (ROS). Evidence shows that inflammation and adaptive immunity are involved in cancer-reducing effects of plasma treatment, but the role of innate immune cells is still unclear. Natural killer (NK)-cells interact with target cells via activating and inhibiting surface receptors and kill in case of dominating activating signals. In this study, we investigated the effect of cold physical plasma (kINPen) on two skin cancer cell lines (A375 and A431), with non-malignant HaCaT keratinocytes as control, and identified a plasma treatment time-dependent toxicity that was more pronounced in the cancer cells. Plasma treatment also modulated the expression of activating and inhibiting receptors more profoundly in skin cancer cells compared to HaCaT cells, leading to significantly higher NK-cell killing rates in the tumor cells. Together with increased pro-inflammatory mediators such as IL-6 and IL-8, we conclude that plasma treatment spurs stress responses in skin cancer cells, eventually augmenting NK-cell activity. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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16 pages, 1692 KiB  
Article
Genome-Wide Comparison of the Target Genes of the Reactive Oxygen Species and Non-Reactive Oxygen Species Constituents of Cold Atmospheric Plasma in Cancer Cells
by Hwee Won Ji, Heejoo Kim, Hyeon Woo Kim, Sung Hwan Yun, Jae Eun Park, Eun Ha Choi and Sun Jung Kim
Cancers 2020, 12(9), 2640; https://doi.org/10.3390/cancers12092640 - 16 Sep 2020
Cited by 11 | Viewed by 2539
Abstract
Cold atmospheric plasma (CAP) can induce cancer cell death. The majority of gene regulation studies have been biased towards reactive oxygen species (ROS) among the physicochemical components of CAP. The current study aimed to systemically determine the distribution of target genes regulated by [...] Read more.
Cold atmospheric plasma (CAP) can induce cancer cell death. The majority of gene regulation studies have been biased towards reactive oxygen species (ROS) among the physicochemical components of CAP. The current study aimed to systemically determine the distribution of target genes regulated by the ROS and non-ROS constituents of CAP. Genome-wide expression data from a public database, which were obtained after treating U937 leukemia and SK-mel-147 melanoma cells with CAP or H2O2, were analyzed, and gene sets regulated by either or both of them were identified. The results showed 252 and 762 genes in H2O2-treated U937 and SK-mel-147 cells, respectively, and 112 and 843 genes in CAP-treated U937 and SK-mel-147 cells, respectively, with expression changes higher than two-fold. Notably, only four and two genes were regulated by H2O2 and CAP in common, respectively, indicating that non-ROS constituents were responsible for the regulation of the majority of CAP-regulated genes. Experiments using ROS and nitrogen oxide synthase (NOS) inhibitors demonstrated the ROS- and reactive nitrogen species (RNS)-independent regulation of PTGER3 and HSPA6 when U937 cancer cells were treated with CAP. Taken together, this study identified CAP-specific genes regulated by constituents other than ROS or RNS and could contribute to the annotation of the target genes of specific constituents in CAP. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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19 pages, 3973 KiB  
Article
Plasma Treatment Limits Human Melanoma Spheroid Growth and Metastasis Independent of the Ambient Gas Composition
by Sybille Hasse, Tita Meder, Eric Freund, Thomas von Woedtke and Sander Bekeschus
Cancers 2020, 12(9), 2570; https://doi.org/10.3390/cancers12092570 - 09 Sep 2020
Cited by 19 | Viewed by 2856
Abstract
Melanoma skin cancer is still a deadly disease despite recent advances in therapy. Previous studies have suggested medical plasma technology as a promising modality for melanoma treatment. However, the efficacy of plasmas operated under different ambient air conditions and the comparison of direct [...] Read more.
Melanoma skin cancer is still a deadly disease despite recent advances in therapy. Previous studies have suggested medical plasma technology as a promising modality for melanoma treatment. However, the efficacy of plasmas operated under different ambient air conditions and the comparison of direct and indirect plasma treatments are mostly unexplored for this tumor entity. Moreover, exactly how plasma treatment affects melanoma metastasis has still not been explained. Using 3D tumor spheroid models and high-content imaging technology, we addressed these questions by utilizing one metastatic and one non-metastatic human melanoma cell line targeted with an argon plasma jet. Plasma treatment was toxic in both cell lines. Modulating the oxygen and nitrogen ambient air composition (100/0, 75/25, 50/50, 25/75, and 0/100) gave similar toxicity and reduced the spheroid growth for all conditions. This was the case for both direct and indirect treatments, with the former showing a treatment time-dependent response while the latter resulted in cytotoxicity with the longest treatment time investigated. Live-cell imaging of in-gel cultured spheroids indicated that plasma treatment did not enhance metastasis, and flow cytometry showed a significant modulation of S100A4 but not in any of the five other metastasis-related markers (β-catenin, E-cadherin, LEF1, SLUG, and ZEB1) investigated. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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19 pages, 3895 KiB  
Article
Plasma Treatment Limits Cutaneous Squamous Cell Carcinoma Development In Vitro and In Vivo
by Gabriella Pasqual-Melo, Thiago Nascimento, Larissa Juliani Sanches, Fernanda Paschoal Blegniski, Julya Karen Bianchi, Sanjeev Kumar Sagwal, Julia Berner, Anke Schmidt, Steffen Emmert, Klaus-Dieter Weltmann, Thomas von Woedtke, Rajesh Kumar Gandhirajan, Alessandra Lourenço Cecchini and Sander Bekeschus
Cancers 2020, 12(7), 1993; https://doi.org/10.3390/cancers12071993 - 21 Jul 2020
Cited by 26 | Viewed by 4226
Abstract
Cutaneous squamous cell carcinoma (SCC) is the most prevalent cancer worldwide, increasing the cost of healthcare services and with a high rate of morbidity. Its etiology is linked to chronic ultraviolet (UV) exposure that leads to malignant transformation of keratinocytes. Invasive growth and [...] Read more.
Cutaneous squamous cell carcinoma (SCC) is the most prevalent cancer worldwide, increasing the cost of healthcare services and with a high rate of morbidity. Its etiology is linked to chronic ultraviolet (UV) exposure that leads to malignant transformation of keratinocytes. Invasive growth and metastasis are severe consequences of this process. Therapy-resistant and highly aggressive SCC is frequently fatal, exemplifying the need for novel treatment strategies. Cold physical plasma is a partially ionized gas, expelling therapeutic doses of reactive oxygen and nitrogen species that were investigated for their anticancer capacity against SCC in vitro and SCC-like lesions in vivo. Using the kINPen argon plasma jet, a selective growth-reducing action of plasma treatment was identified in two SCC cell lines in 2D and 3D cultures. In vivo, plasma treatment limited the progression of UVB-induced SSC-like skin lesions and dermal degeneration without compromising lesional or non-lesional skin. In lesional tissue, this was associated with a decrease in cell proliferation and the antioxidant transcription factor Nrf2 following plasma treatment, while catalase expression was increased. Analysis of skin adjacent to the lesions and determination of global antioxidant parameters confirmed the local but not systemic action of the plasma anticancer therapy in vivo. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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20 pages, 3780 KiB  
Article
Combination Treatment with Cold Physical Plasma and Pulsed Electric Fields Augments ROS Production and Cytotoxicity in Lymphoma
by Christina M. Wolff, Juergen F. Kolb, Klaus-Dieter Weltmann, Thomas von Woedtke and Sander Bekeschus
Cancers 2020, 12(4), 845; https://doi.org/10.3390/cancers12040845 - 31 Mar 2020
Cited by 29 | Viewed by 3665
Abstract
New approaches in oncotherapy rely on the combination of different treatments to enhance the efficacy of established monotherapies. Pulsed electric fields (PEFs) are an established method (electrochemotherapy) for enhancing cellular drug uptake while cold physical plasma is an emerging and promising anticancer technology. [...] Read more.
New approaches in oncotherapy rely on the combination of different treatments to enhance the efficacy of established monotherapies. Pulsed electric fields (PEFs) are an established method (electrochemotherapy) for enhancing cellular drug uptake while cold physical plasma is an emerging and promising anticancer technology. This study aimed to combine both technologies to elucidate their cytotoxic potential as well as the underlying mechanisms of the effects observed. An electric field generator (0.9–1.0 kV/cm and 100-μs pulse duration) and an atmospheric pressure argon plasma jet were employed for the treatment of lymphoma cell lines as a model system. PEF but not plasma treatment induced cell membrane permeabilization. Additive cytotoxicity was observed for the metabolic activity and viability of the cells while the sequence of treatment in the combination played only a minor role. Intriguingly, a parallel combination was more effective compared to a 15-min pause between both treatment regimens. A combination effect was also found for lipid peroxidation; however, none could be observed in the cytosolic and mitochondrial reactive oxygen species (ROS) production. The supplementation with either antioxidant, a pan-caspase-inhibitor or a ferroptosis inhibitor, all partially rescued lymphoma cells from terminal cell death, which contributes to the mechanistic understanding of this combination treatment. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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Review

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19 pages, 7501 KiB  
Review
Plasma-Treated Solutions (PTS) in Cancer Therapy
by Hiromasa Tanaka, Sander Bekeschus, Dayun Yan, Masaru Hori, Michael Keidar and Mounir Laroussi
Cancers 2021, 13(7), 1737; https://doi.org/10.3390/cancers13071737 - 06 Apr 2021
Cited by 69 | Viewed by 5024
Abstract
Cold physical plasma is a partially ionized gas generating various reactive oxygen and nitrogen species (ROS/RNS) simultaneously. ROS/RNS have therapeutic effects when applied to cells and tissues either directly from the plasma or via exposure to solutions that have been treated beforehand using [...] Read more.
Cold physical plasma is a partially ionized gas generating various reactive oxygen and nitrogen species (ROS/RNS) simultaneously. ROS/RNS have therapeutic effects when applied to cells and tissues either directly from the plasma or via exposure to solutions that have been treated beforehand using plasma processes. This review addresses the challenges and opportunities of plasma-treated solutions (PTSs) for cancer treatment. These PTSs include plasma-treated cell culture media in experimental research as well as clinically approved solutions such as saline and Ringer’s lactate, which, in principle, already qualify for testing in therapeutic settings. Several types of cancers were found to succumb to the toxic action of PTSs, suggesting a broad mechanism of action based on the tumor-toxic activity of ROS/RNS stored in these solutions. Moreover, it is indicated that the PTS has immuno-stimulatory properties. Two different routes of application are currently envisaged in the clinical setting. One is direct injection into the bulk tumor, and the other is lavage in patients suffering from peritoneal carcinomatosis adjuvant to standard chemotherapy. While many promising results have been achieved so far, several obstacles, such as the standardized generation of large volumes of sterile PTS, remain to be addressed. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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17 pages, 6725 KiB  
Review
Plasma-Conditioned Liquids as Anticancer Therapies In Vivo: Current State and Future Directions
by Xavi Solé-Martí, Albert Espona-Noguera, Maria-Pau Ginebra and Cristina Canal
Cancers 2021, 13(3), 452; https://doi.org/10.3390/cancers13030452 - 25 Jan 2021
Cited by 30 | Viewed by 3497
Abstract
Plasma-conditioned liquids (PCL) are gaining increasing attention in the medical field, especially in oncology, and translation to the clinics is advancing on a good path. This emerging technology involving cold plasmas has great potential as a therapeutic approach in cancer diseases, as PCL [...] Read more.
Plasma-conditioned liquids (PCL) are gaining increasing attention in the medical field, especially in oncology, and translation to the clinics is advancing on a good path. This emerging technology involving cold plasmas has great potential as a therapeutic approach in cancer diseases, as PCL have been shown to selectively kill cancer cells by triggering apoptotic mechanisms without damaging healthy cells. In this context, PCL can be injected near the tumor or intratumorally, thereby allowing the treatment of malignant tumors located in internal organs that are not accessible for direct cold atmospheric plasma (CAP) treatment. Therefore, PCL constitutes a very interesting and minimally invasive alternative to direct CAP treatment in cancer therapy, avoiding surgeries and allowing multiple local administrations. As the field advances, it is progressively moving to the evaluation of the therapeutic effects of PCL in in vivo scenarios. Exciting developments are pushing forward the clinical translation of this novel therapy. However, there is still room for research, as the quantification and identification of reactive oxygen and nitrogen species (RONS) in in vivo conditions is not yet clarified, dosage regimens are highly variable among studies, and other more relevant in vivo models could be used. In this context, this work aims to present a critical review of the state of the field of PCL as anticancer agents applied in in vivo studies. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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14 pages, 2425 KiB  
Review
Cold Atmospheric Plasma: A Promising Controller of Cancer Cell States
by Xiaofeng Dai, Kateryna Bazaka, Erik W. Thompson and Kostya (Ken) Ostrikov
Cancers 2020, 12(11), 3360; https://doi.org/10.3390/cancers12113360 - 13 Nov 2020
Cited by 52 | Viewed by 3933
Abstract
Rich in reactive oxygen and nitrogen species, cold atmospheric plasma has been shown to effectively control events critical to cancer progression; selectively inducing apoptosis, reducing tumor volume and vasculature, and halting metastasis by taking advantage of, e.g., synergies between hydrogen peroxide and nitrites. [...] Read more.
Rich in reactive oxygen and nitrogen species, cold atmospheric plasma has been shown to effectively control events critical to cancer progression; selectively inducing apoptosis, reducing tumor volume and vasculature, and halting metastasis by taking advantage of, e.g., synergies between hydrogen peroxide and nitrites. This paper discusses the efficacy, safety and administration of cold atmospheric plasma treatment as a potential tool against cancers, with a focus on the mechanisms by which cold atmospheric plasma may affect critical transitional switches that govern tumorigenesis: the life/death control, tumor angiogenesis and epithelial–mesenchymal transition, and drug sensitivity spectrum. We introduce the possibility of modeling cell transitions between the normal and cancerous states using cold atmospheric plasma as a novel research avenue to enhance our understanding of plasma-aided control of oncogenesis. Full article
(This article belongs to the Special Issue Advances in Plasma Oncology toward Clinical Translation)
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