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3 pages, 175 KiB

Open AccessEditorial

Plasma in Cancer Treatment

by Angela Privat-Maldonado and Annemie Bogaerts

Cancers 2020, 12(9), 2617; https://doi.org/10.3390/cancers12092617 - 14 Sep 2020

Cited by 9 | Viewed by 2146

Abstract

Cancer is the second leading cause of death worldwide, and while science has advanced significantly to improve the treatment outcome and quality of life in cancer patients, there are still many issues with the current therapies, such as toxicity and the development of [...] Read more.

Cancer is the second leading cause of death worldwide, and while science has advanced significantly to improve the treatment outcome and quality of life in cancer patients, there are still many issues with the current therapies, such as toxicity and the development of resistance to treatment [...] Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

Research

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21 pages, 4633 KiB

Open AccessArticle

Cold-Atmospheric Plasma Induces Tumor Cell Death in Preclinical In Vivo and In Vitro Models of Human Cholangiocarcinoma

by Javier Vaquero, Florian Judée, Marie Vallette, Henri Decauchy, Ander Arbelaiz, Lynda Aoudjehane, Olivier Scatton, Ester Gonzalez-Sanchez, Fatiha Merabtene, Jérémy Augustin, Chantal Housset, Thierry Dufour and Laura Fouassier

Cancers 2020, 12(5), 1280; https://doi.org/10.3390/cancers12051280 - 19 May 2020

Cited by 47 | Viewed by 6200

Abstract

Through the last decade, cold atmospheric plasma (CAP) has emerged as an innovative therapeutic option for cancer treatment. Recently, we have set up a potentially safe atmospheric pressure plasma jet device that displays antitumoral properties in a preclinical model of cholangiocarcinoma (CCA), a [...] Read more.

Through the last decade, cold atmospheric plasma (CAP) has emerged as an innovative therapeutic option for cancer treatment. Recently, we have set up a potentially safe atmospheric pressure plasma jet device that displays antitumoral properties in a preclinical model of cholangiocarcinoma (CCA), a rare and very aggressive cancer emerging from the biliary tree with few efficient treatments. In the present study, we aimed at deciphering the molecular mechanisms underlying the antitumor effects of CAP towards CCA in both an in vivo and in vitro context. In vivo, using subcutaneous xenografts into immunocompromised mice, CAP treatment of CCA induced DNA lesions and tumor cell apoptosis, as evaluated by 8-oxoguanine and cleaved caspase-3 immunohistochemistry, respectively. The analysis of the tumor microenvironment showed changes in markers related to macrophage polarization. In vitro, the incubation of CCA cells with CAP-treated culture media (i.e., plasma-activated media, PAM) led to a dose response decrease in cell survival. At molecular level, CAP treatment induced double-strand DNA breaks, followed by an increased phosphorylation and activation of the cell cycle master regulators CHK1 and p53, leading to cell cycle arrest and cell death by apoptosis. In conclusion, CAP is a novel therapeutic option to consider for CCA in the future. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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15 pages, 1642 KiB

Open AccessArticle

Cancer-Selective Treatment of Cancerous and Non-Cancerous Human Cervical Cell Models by a Non-Thermally Operated Electrosurgical Argon Plasma Device

by Lukas Feil, André Koch, Raphael Utz, Michael Ackermann, Jakob Barz, Matthias Stope, Bernhard Krämer, Diethelm Wallwiener, Sara Y. Brucker and Martin Weiss

Cancers 2020, 12(4), 1037; https://doi.org/10.3390/cancers12041037 - 23 Apr 2020

Cited by 24 | Viewed by 3714

Abstract

Cold atmospheric plasma (CAP) treatment is developing as a promising option for local anti-neoplastic treatment of dysplastic lesions and early intraepithelial cancer. Currently, high-frequency electrosurgical argon plasma sources are available and well established for clinical use. In this study, we investigated the effects [...] Read more.

Cold atmospheric plasma (CAP) treatment is developing as a promising option for local anti-neoplastic treatment of dysplastic lesions and early intraepithelial cancer. Currently, high-frequency electrosurgical argon plasma sources are available and well established for clinical use. In this study, we investigated the effects of treatment with a non-thermally operated electrosurgical argon plasma source, a Martin Argon Plasma Beamer System (MABS), on cell proliferation and metabolism of a tissue panel of human cervical cancer cell lines as well as on non-cancerous primary cells of the cervix uteri. Similar to conventional CAP sources, we were able to show that MABS was capable of causing antiproliferative and cytotoxic effects on cervical squamous cell and adenocarcinoma as well as on non-neoplastic cervical tissue cells due to the generation of reactive species. Notably, neoplastic cells were more sensitive to the MABS treatment, suggesting a promising new and non-invasive application for in vivo treatment of precancerous and cancerous cervical lesions with non-thermally operated electrosurgical argon plasma sources. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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15 pages, 2214 KiB

Open AccessArticle

Anti-Cancer Potential of Two Plasma-Activated Liquids: Implication of Long-Lived Reactive Oxygen and Nitrogen Species

by Elena Griseti, Nofel Merbahi and Muriel Golzio

Cancers 2020, 12(3), 721; https://doi.org/10.3390/cancers12030721 - 19 Mar 2020

Cited by 46 | Viewed by 4007

Abstract

Cold atmospheric plasma-exposed culture medium may efficiently kill cancer cells in vitro. Due to the complexity of the medium obtained after plasma exposure, less complex physiological liquids, such as saline solutions and saline buffers, are gathering momentum. Among the plethora of reactive oxygen [...] Read more.

Cold atmospheric plasma-exposed culture medium may efficiently kill cancer cells in vitro. Due to the complexity of the medium obtained after plasma exposure, less complex physiological liquids, such as saline solutions and saline buffers, are gathering momentum. Among the plethora of reactive oxygen and nitrogen species (RONS) that are produced in these plasma-activated liquids, hydrogen peroxide, nitrite and nitrate appear to be mainly responsible for cytotoxic and genotoxic effects. Here, we evaluated the anti-cancer potential of plasma-activated phosphate-buffered saline (P-A PBS) and sodium chloride 0.9% (P-A NaCl), using a three-dimensional tumor model. Two epithelial cancer cell lines were used to evaluate cellular effects of either P-A PBS or P-A NaCl. Human colorectal cancer cells HCT 116 and human ovarian carcinoma, SKOV-3 were used to investigate the manner by which different cell types respond to different plasma-activated liquids treatments. Our investigations indicate that P-A PBS is more efficient than P-A NaCl mainly because RONS are produced in larger quantities. Indeed, we show that the cytotoxicity of these liquids directly correlates with the concentration of hydrogen peroxide and nitrite. Moreover, P-A PBS induced a faster-occurring and more pronounced cell death, which arose within deeper layers of the 3D multicellular spheroid models. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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15 pages, 4495 KiB

Open AccessArticle

Plasma-activated Ringer’s Lactate Solution Displays a Selective Cytotoxic Effect on Ovarian Cancer Cells

by Alina Bisag, Cristiana Bucci, Sara Coluccelli, Giulia Girolimetti, Romolo Laurita, Pierandrea De Iaco, Anna Myriam Perrone, Matteo Gherardi, Lorena Marchio, Anna Maria Porcelli, Vittorio Colombo and Giuseppe Gasparre

Cancers 2020, 12(2), 476; https://doi.org/10.3390/cancers12020476 - 18 Feb 2020

Cited by 39 | Viewed by 4101

Abstract

Epithelial Ovarian Cancer (EOC) is one of the leading causes of cancer-related deaths among women and is characterized by the diffusion of nodules or plaques from the ovary to the peritoneal surfaces. Conventional therapeutic options cannot eradicate the disease and show low efficacy [...] Read more.

Epithelial Ovarian Cancer (EOC) is one of the leading causes of cancer-related deaths among women and is characterized by the diffusion of nodules or plaques from the ovary to the peritoneal surfaces. Conventional therapeutic options cannot eradicate the disease and show low efficacy against resistant tumor subclones. The treatment of liquids via cold atmospheric pressure plasma enables the production of plasma-activated liquids (PALs) containing reactive oxygen and nitrogen species (RONS) with selective anticancer activity. Thus, the delivery of RONS to cancer tissues by intraperitoneal washing with PALs might be an innovative strategy for the treatment of EOC. In this work, plasma-activated Ringer’s Lactate solution (PA-RL) was produced by exposing a liquid substrate to a multiwire plasma source. Subsequently, PA-RL dilutions are used for the treatment of EOC, non-cancer and fibroblast cell lines, revealing a selectivity of PA-RL, which induces a significantly higher cytotoxic effect in EOC with respect to non-cancer cells. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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14 pages, 4672 KiB

Open AccessArticle

Cold Atmospheric Plasma and Gold Quantum Dots Exert Dual Cytotoxicity Mediated by the Cell Receptor-Activated Apoptotic Pathway in Glioblastoma Cells

by Nagendra Kumar Kaushik, Neha Kaushik, Rizwan Wahab, Pradeep Bhartiya, Nguyen Nhat Linh, Farheen Khan, Abdulaziz A. Al-Khedhairy and Eun Ha Choi

Cancers 2020, 12(2), 457; https://doi.org/10.3390/cancers12020457 - 16 Feb 2020

Cited by 28 | Viewed by 3973

Abstract

Brain cancer malignancies represent an immense challenge for research and clinical oncology. Glioblastoma is the most lethal form of primary malignant brain cancer and is one of the most aggressive forms commonly associated with adverse prognosis and fatal outcome. Currently, combinations of inorganic [...] Read more.

Brain cancer malignancies represent an immense challenge for research and clinical oncology. Glioblastoma is the most lethal form of primary malignant brain cancer and is one of the most aggressive forms commonly associated with adverse prognosis and fatal outcome. Currently, combinations of inorganic and organic nanomaterials have been shown to improve survival rates through targeted drug delivery systems. In this study, we developed a dual treatment approach using cold atmospheric plasma (CAP) and gold quantum dots (AuQDs) for brain cancer. Our results showed that CAP and AuQDs induced dual cytotoxicity in brain cancer cells via Fas/TRAIL-mediated cell death receptor pathways. Moreover, combination treatment with CAP and AuQDs suppressed the motility and sphere-formation of brain cancer cells, which are recognized indicators of cancer aggressiveness. Taken together, the application of AuQDs can improve the efficiency of CAP against brain cancer cells, posing an excellent opportunity for advancing the treatment of aggressive glioblastomas. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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19 pages, 3663 KiB

Open AccessArticle

Synergy between Non-Thermal Plasma with Radiation Therapy and Olaparib in a Panel of Breast Cancer Cell Lines

by Julie Lafontaine, Jean-Sébastien Boisvert, Audrey Glory, Sylvain Coulombe and Philip Wong

Cancers 2020, 12(2), 348; https://doi.org/10.3390/cancers12020348 - 4 Feb 2020

Cited by 25 | Viewed by 3963

Abstract

Cancer therapy has evolved to a more targeted approach and often involves drug combinations to achieve better response rates. Non-thermal plasma (NTP), a technology rapidly expanding its application in the medical field, is a near room temperature ionized gas capable of producing reactive [...] Read more.

Cancer therapy has evolved to a more targeted approach and often involves drug combinations to achieve better response rates. Non-thermal plasma (NTP), a technology rapidly expanding its application in the medical field, is a near room temperature ionized gas capable of producing reactive species, and can induce cancer cell death both in vitro and in vivo. Here, we used proliferation assay to characterize the plasma sensitivity of fourteen breast cancer cell lines. These assays showed that all tested cell lines were sensitive to NTP. In addition, a good correlation was found comparing cell sensitivity to NTP and radiation therapy (RT), where cells that were sensitive to RT were also sensitive to plasma. Moreover, in some breast cancer cell lines, NTP and RT have a synergistic effect. Adding a dose of PARP-inhibitor olaparib to NTP treatment always increases the efficacy of the treatment. Olaparib also exhibits a synergistic effect with NTP, especially in triple negative breast cancer cells. Results presented here help elucidate the position of plasma use as a potential breast cancer treatment. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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16 pages, 2860 KiB

Open AccessArticle

Trans-Mucosal Efficacy of Non-Thermal Plasma Treatment on Cervical Cancer Tissue and Human Cervix Uteri by a Next Generation Electrosurgical Argon Plasma Device

by Thomas Wenzel, Daniel A. Carvajal Berrio, Christl Reisenauer, Shannon Layland, André Koch, Diethelm Wallwiener, Sara Y. Brucker, Katja Schenke-Layland, Eva-Maria Brauchle and Martin Weiss

Cancers 2020, 12(2), 267; https://doi.org/10.3390/cancers12020267 - 22 Jan 2020

Cited by 25 | Viewed by 3853

Abstract

Non-invasive physical plasma (NIPP) generated by non-thermally operated electrosurgical argon plasma sources is a promising treatment for local chronic inflammatory, precancerous and cancerous diseases. NIPP-enabling plasma sources are highly available and medically approved. The purpose of this study is the investigation of the [...] Read more.

Non-invasive physical plasma (NIPP) generated by non-thermally operated electrosurgical argon plasma sources is a promising treatment for local chronic inflammatory, precancerous and cancerous diseases. NIPP-enabling plasma sources are highly available and medically approved. The purpose of this study is the investigation of the effects of non-thermal NIPP on cancer cell proliferation, viability and apoptosis and the identification of the underlying biochemical and molecular modes of action. For this, cervical cancer (CC) single cells and healthy human cervical tissue were analyzed by cell counting, caspase activity assays, microscopic and flow-cytometric viability measurements and molecular tissue characterization using Raman imaging. NIPP treatment caused an immediate and persisting decrease in CC cell growth and cell viability associated with significant plasma-dependent effects on lipid structures. These effects could also be identified in primary cells from healthy cervical tissue and could be traced into the basal cell layer of superficially NIPP-treated cervical mucosa. This study shows that NIPP treatment with non-thermally operated electrosurgical argon plasma devices is a promising method for the treatment of human mucosa, inducing specific molecular changes in cells. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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13 pages, 2239 KiB

Open AccessArticle

Non-Thermal Atmospheric Pressure Bio-Compatible Plasma Stimulates Apoptosis via p38/MAPK Mechanism in U87 Malignant Glioblastoma

by Mahmuda Akter, Anshika Jangra, Seung Ah Choi, Eun Ha Choi and Ihn Han

Cancers 2020, 12(1), 245; https://doi.org/10.3390/cancers12010245 - 19 Jan 2020

Cited by 52 | Viewed by 5043

Abstract

Nonthermal plasma is a promising novel therapy for the alteration of biological and clinical functions of cells and tissues, including apoptosis and inhibition of tumor progression. This therapy generates reactive oxygen and nitrogen species (RONS), which play a major role in anticancer effects. [...] Read more.

Nonthermal plasma is a promising novel therapy for the alteration of biological and clinical functions of cells and tissues, including apoptosis and inhibition of tumor progression. This therapy generates reactive oxygen and nitrogen species (RONS), which play a major role in anticancer effects. Previous research has verified that plasma jets can selectively induce apoptosis in various cancer cells, suggesting that it could be a potentially effective novel therapy in combination with or as an alternative to conventional therapeutic methods. In this study, we determined the effects of nonthermal air soft plasma jets on a U87 MG brain cancer cell line, including the dose- and time-dependent effects and the physicochemical and biological correlation between the RONS cascade and p38/mitogen-activated protein kinase (MAPK) signaling pathway, which contribute to apoptosis. The results indicated that soft plasma jets efficiently inhibit cell proliferation and induce apoptosis in U87 MG cells but have minimal effects on astrocytes. These findings revealed that soft plasma jets produce a potent cytotoxic effect via the initiation of cell cycle arrest and apoptosis. The production of reactive oxygen species (ROS) in cells was tested, and an intracellular ROS scavenger, N-acetyl cysteine (NAC), was examined. Our results suggested that soft plasma jets could potentially be used as an effective approach for anticancer therapy. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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19 pages, 1680 KiB

Open AccessArticle

Cold Plasma-Treated Ringer’s Saline: A Weapon to Target Osteosarcoma

by Miguel Mateu-Sanz, Juan Tornín, Bénédicte Brulin, Anna Khlyustova, Maria-Pau Ginebra, Pierre Layrolle and Cristina Canal

Cancers 2020, 12(1), 227; https://doi.org/10.3390/cancers12010227 - 17 Jan 2020

Cited by 61 | Viewed by 6796

Abstract

Osteosarcoma (OS) is the main primary bone cancer, presenting poor prognosis and difficult treatment. An innovative therapy may be found in cold plasmas, which show anti-cancer effects related to the generation of reactive oxygen and nitrogen species in liquids. In vitro models are [...] Read more.

Osteosarcoma (OS) is the main primary bone cancer, presenting poor prognosis and difficult treatment. An innovative therapy may be found in cold plasmas, which show anti-cancer effects related to the generation of reactive oxygen and nitrogen species in liquids. In vitro models are based on the effects of plasma-treated culture media on cell cultures. However, effects of plasma-activated saline solutions with clinical application have not yet been explored in OS. The aim of this study is to obtain mechanistic insights on the action of plasma-activated Ringer’s saline (PAR) for OS therapy in cell and organotypic cultures. To that aim, cold atmospheric plasma jets were used to obtain PAR, which produced cytotoxic effects in human OS cells (SaOS-2, MG-63, and U2-OS), related to the increasing concentration of reactive oxygen and nitrogen species generated. Proof of selectivity was found in the sustained viability of hBM-MSCs with the same treatments. Organotypic cultures of murine OS confirmed the time-dependent cytotoxicity observed in 2D. Histological analysis showed a decrease in proliferating cells (lower Ki-67 expression). It is shown that the selectivity of PAR is highly dependent on the concentrations of reactive species, being the differential intracellular reactive oxygen species increase and DNA damage between OS cells and hBM-MSCs key mediators for cell apoptosis. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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21 pages, 8275 KiB

Open AccessArticle

Cell Electropermeabilisation Enhancement by Non-Thermal-Plasma-Treated PBS

by Thai-Hoa Chung, Augusto Stancampiano, Kyriakos Sklias, Kristaq Gazeli, Franck M. André, Sébastien Dozias, Claire Douat, Jean-Michel Pouvesle, João Santos Sousa, Éric Robert and Lluis M. Mir

Cancers 2020, 12(1), 219; https://doi.org/10.3390/cancers12010219 - 16 Jan 2020

Cited by 53 | Viewed by 4240

Abstract

The effectiveness of electrochemotherapy (ECT) in local eradication of tumours in human and veterinary medicine has been proven. ECT consists of increasing the uptake of cytotoxic drugs by means of pulsed electric fields (PEFs) that transiently permeabilise the cell membrane. Still, this tumour [...] Read more.

The effectiveness of electrochemotherapy (ECT) in local eradication of tumours in human and veterinary medicine has been proven. ECT consists of increasing the uptake of cytotoxic drugs by means of pulsed electric fields (PEFs) that transiently permeabilise the cell membrane. Still, this tumour treatment includes some drawbacks that are linked to the characteristics of the intense electric pulses (EPs) used. Meanwhile, the emerging field of cancer therapies that are based on the application of non-thermal plasmas (NTP) has recently garnered interest because of their potentialities as rich sources of reactive species. In this work, we investigated the potential capabilities of the combined application of indirect NTP treatment and microsecond PEFs (µsPEFs) to outperform in vitro cell electropermeabilisation, the basis of ECT. Thus, phosphate-buffered saline (PBS) was plasma-treated (pPBS) and used afterwards to explore the effects of its combination with µsPEFs. Analysis of two different cell lines (DC-3F Chinese hamster lung fibroblasts and malignant B16-F10 murine melanoma cells), by flow cytometry, revealed that this combination resulted in significant increases of the level of cell membrane electropermeabilisation, even at very low electric field amplitude. The B16-F10 cells were more sensitive to the combined treatment than DC-3F cells. Importantly, the percentage of permeabilised cells reached values similar to those of cells exposed to classical electroporation field amplitude (1100 V/cm) when the cells were treated with pPBS before and after being exposed only to very low PEF amplitude (600 V/cm). Although the level of permeabilisation of the cells that are treated by the pPBS and the PEFs at 600 V/cm is lower than the level reached after the exposure to µsPEFs alone at 1100 V/cm, the combined treatment opens the possibility to reduce the amplitude of the EPs used in ECT, potentially allowing for a novel ECT with reduced side-effects. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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19 pages, 2972 KiB

Open AccessArticle

Gas Plasma-Conditioned Ringer’s Lactate Enhances the Cytotoxic Activity of Cisplatin and Gemcitabine in Pancreatic Cancer In Vitro and In Ovo

by Kim-Rouven Liedtke, Eric Freund, Maraike Hermes, Stefan Oswald, Claus-Dieter Heidecke, Lars-Ivo Partecke and Sander Bekeschus

Cancers 2020, 12(1), 123; https://doi.org/10.3390/cancers12010123 - 2 Jan 2020

Cited by 33 | Viewed by 4296

Abstract

Pancreatic cancer is one of the most aggressive tumor entities. Diffuse metastatic infiltration of vessels and the peritoneum restricts curative surgery. Standard chemotherapy protocols include the cytostatic drug gemcitabine with limited efficacy at considerable toxicity. In search of a more effective and less [...] Read more.

Pancreatic cancer is one of the most aggressive tumor entities. Diffuse metastatic infiltration of vessels and the peritoneum restricts curative surgery. Standard chemotherapy protocols include the cytostatic drug gemcitabine with limited efficacy at considerable toxicity. In search of a more effective and less toxic treatment modality, we tested in human pancreatic cancer cells (MiaPaca and PaTuS) a novel combination therapy consisting of cytostatic drugs (gemcitabine or cisplatin) and gas plasma-conditioned Ringer’s lactate that acts via reactive oxygen species. A decrease in metabolic activity and viability, change in morphology, and cell cycle arrest was observed in vitro. The combination treatment was found to be additively toxic. The findings were validated utilizing an in ovo tumor model of solid pancreatic tumors growing on the chorion-allantois membrane of fertilized chicken eggs (TUM-CAM). The combination of the drugs (especially cisplatin) with the plasma-conditioned liquid significantly enhanced the anti-cancer effects, resulting in the induction of cell death, cell cycle arrest, and inhibition of cell growth with both of the cell lines tested. In conclusion, our novel combination approach may be a promising new avenue to increase the tolerability and efficacy of locally applied chemotherapeutic in diffuse metastatic peritoneal carcinomatosis of the pancreas. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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26 pages, 3738 KiB

Open AccessArticle

Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro

by Eric Freund, Kim-Rouven Liedtke, Lea Miebach, Kristian Wende, Amanda Heidecke, Nagendra Kumar Kaushik, Eun Ha Choi, Lars-Ivo Partecke and Sander Bekeschus

Cancers 2020, 12(1), 122; https://doi.org/10.3390/cancers12010122 - 2 Jan 2020

Cited by 16 | Viewed by 5013

Abstract

Colorectal carcinoma is among the most common types of cancers. With this disease, diffuse scattering in the abdominal area (peritoneal carcinosis) often occurs before diagnosis, making surgical removal of the entire malignant tissue impossible due to a large number of tumor nodules. Previous [...] Read more.

Colorectal carcinoma is among the most common types of cancers. With this disease, diffuse scattering in the abdominal area (peritoneal carcinosis) often occurs before diagnosis, making surgical removal of the entire malignant tissue impossible due to a large number of tumor nodules. Previous treatment options include radiation and its combination with intraperitoneal heat-induced chemotherapy (HIPEC). Both options have strong side effects and are often poor in therapeutic efficacy. Tumor cells often grow and proliferate dysregulated, with enzymes of the protein kinase family often playing a crucial role. The present study investigated whether a combination of protein kinase inhibitors and low-dose induction of oxidative stress (using hydrogen peroxide, H₂O₂) has an additive cytotoxic effect on murine, colorectal tumor cells (CT26). Protein kinase inhibitors from a library of 80 substances were used to investigate colorectal cancer cells for their activity, morphology, and immunogenicity (immunogenic cancer cell death, ICD) upon mono or combination. Toxic compounds identified in 2D cultures were confirmed in 3D cultures, and additive cytotoxicity was identified for the substances lavendustin A, GF109203X, and rapamycin. Toxicity was concomitant with cell cycle arrest, but except HMGB1, no increased expression of immunogenic markers was identified with the combination treatment. The results were validated for GF109203X and rapamycin but not lavendustin A in the 3D model of different colorectal (HT29, SW480) and pancreatic cancer cell lines (MiaPaca, Panc01). In conclusion, our in vitro data suggest that combining oxidative stress with chemotherapy would be conceivable to enhance antitumor efficacy in HIPEC. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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13 pages, 3824 KiB

Open AccessArticle

Cold Atmospheric Plasma Restores Paclitaxel Sensitivity to Paclitaxel-Resistant Breast Cancer Cells by Reversing Expression of Resistance-Related Genes

by Sungbin Park, Heejoo Kim, Hwee Won Ji, Hyeon Woo Kim, Sung Hwan Yun, Eun Ha Choi and Sun Jung Kim

Cancers 2019, 11(12), 2011; https://doi.org/10.3390/cancers11122011 - 13 Dec 2019

Cited by 30 | Viewed by 3414

Abstract

Paclitaxel (Tx) is a widely used therapeutic chemical for breast cancer treatment; however, cancer recurrence remains an obstacle for improved prognosis of cancer patients. In this study, cold atmospheric plasma (CAP) was tested for its potential to overcome the drug resistance. After developing [...] Read more.

Paclitaxel (Tx) is a widely used therapeutic chemical for breast cancer treatment; however, cancer recurrence remains an obstacle for improved prognosis of cancer patients. In this study, cold atmospheric plasma (CAP) was tested for its potential to overcome the drug resistance. After developing Tx-resistant MCF-7 (MCF-7/TxR) breast cancer cells, CAP was applied to the cells, and its effect on the recovery of drug sensitivity was assessed in both cellular and molecular aspects. Sensitivity to Tx in the MCF-7/TxR cells was restored up to 73% by CAP. A comparison of genome-wide expression profiles between the TxR cells and the CAP-treated cells identified 49 genes that commonly appeared with significant changes. Notably, 20 genes, such as KIF13B, GOLM1, and TLE4, showed opposite expression profiles. The protein expression levels of selected genes, DAGLA and CEACAM1, were recovered to those of their parental cells by CAP. Taken together, CAP inhibited the growth of MCF-7/TxR cancer cells and recovered Tx sensitivity by resetting the expression of multiple drug resistance–related genes. These findings may contribute to extending the application of CAP to the treatment of TxR cancer. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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16 pages, 2094 KiB

Open AccessArticle

Cold Atmospheric Plasma-Treated PBS Eliminates Immunosuppressive Pancreatic Stellate Cells and Induces Immunogenic Cell Death of Pancreatic Cancer Cells

by Jinthe Van Loenhout, Tal Flieswasser, Laurie Freire Boullosa, Jorrit De Waele, Jonas Van Audenaerde, Elly Marcq, Julie Jacobs, Abraham Lin, Eva Lion, Heleen Dewitte, Marc Peeters, Sylvia Dewilde, Filip Lardon, Annemie Bogaerts, Christophe Deben and Evelien Smits

Cancers 2019, 11(10), 1597; https://doi.org/10.3390/cancers11101597 - 19 Oct 2019

Cited by 82 | Viewed by 6552

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a low response to treatment and a five-year survival rate below 5%. The ineffectiveness of treatment is partly because of an immunosuppressive tumor microenvironment, which comprises tumor-supportive pancreatic stellate cells (PSCs). [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a low response to treatment and a five-year survival rate below 5%. The ineffectiveness of treatment is partly because of an immunosuppressive tumor microenvironment, which comprises tumor-supportive pancreatic stellate cells (PSCs). Therefore, new therapeutic strategies are needed to tackle both the immunosuppressive PSC and pancreatic cancer cells (PCCs). Recently, physical cold atmospheric plasma consisting of reactive oxygen and nitrogen species has emerged as a novel treatment option for cancer. In this study, we investigated the cytotoxicity of plasma-treated phosphate-buffered saline (pPBS) using three PSC lines and four PCC lines and examined the immunogenicity of the induced cell death. We observed a decrease in the viability of PSC and PCC after pPBS treatment, with a higher efficacy in the latter. Two PCC lines expressed and released damage-associated molecular patterns characteristic of the induction of immunogenic cell death (ICD). In addition, pPBS-treated PCC were highly phagocytosed by dendritic cells (DCs), resulting in the maturation of DC. This indicates the high potential of pPBS to trigger ICD. In contrast, pPBS induced no ICD in PSC. In general, pPBS treatment of PCCs and PSCs created a more immunostimulatory secretion profile (higher TNF-α and IFN-γ, lower TGF-β) in coculture with DC. Altogether, these data show that plasma treatment via pPBS has the potential to induce ICD in PCCs and to reduce the immunosuppressive tumor microenvironment created by PSCs. Therefore, these data provide a strong experimental basis for further in vivo validation, which might potentially open the way for more successful combination strategies with immunotherapy for PDAC. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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15 pages, 2830 KiB

Open AccessArticle

The Influence of Cell Type and Culture Medium on Determining Cancer Selectivity of Cold Atmospheric Plasma Treatment

by Eline Biscop, Abraham Lin, Wilma Van Boxem, Jinthe Van Loenhout, Joey De Backer, Christophe Deben, Sylvia Dewilde, Evelien Smits and Annemie Bogaerts

Cancers 2019, 11(9), 1287; https://doi.org/10.3390/cancers11091287 - 1 Sep 2019

Cited by 86 | Viewed by 6244

Abstract

Increasing the selectivity of cancer treatments is attractive, as it has the potential to reduce side-effects of therapy. Cold atmospheric plasma (CAP) is a novel cancer treatment that disrupts the intracellular oxidative balance. Several reports claim CAP treatment to be selective, but retrospective [...] Read more.

Increasing the selectivity of cancer treatments is attractive, as it has the potential to reduce side-effects of therapy. Cold atmospheric plasma (CAP) is a novel cancer treatment that disrupts the intracellular oxidative balance. Several reports claim CAP treatment to be selective, but retrospective analysis of these studies revealed discrepancies in several biological factors and culturing methods. Before CAP can be conclusively stated as a selective cancer treatment, the importance of these factors must be investigated. In this study, we evaluated the influence of the cell type, cancer type, and cell culture medium on direct and indirect CAP treatment. Comparison of cancerous cells with their non-cancerous counterparts was performed under standardized conditions to determine selectivity of treatment. Analysis of seven human cell lines (cancerous: A549, U87, A375, and Malme-3M; non-cancerous: BEAS-2B, HA, and HEMa) and five different cell culture media (DMEM, RPMI1640, AM, BEGM, and DCBM) revealed that the tested parameters strongly influence indirect CAP treatment, while direct treatment was less affected. Taken together, the results of our study demonstrate that cell type, cancer type, and culturing medium must be taken into account before selectivity of CAP treatment can be claimed and overlooking these parameters can easily result in inaccurate conclusions of selectivity. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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19 pages, 5093 KiB

Open AccessFeature PaperArticle

Risk Assessment of kINPen Plasma Treatment of Four Human Pancreatic Cancer Cell Lines with Respect to Metastasis

by Sander Bekeschus, Eric Freund, Chiara Spadola, Angela Privat-Maldonado, Christine Hackbarth, Annemie Bogaerts, Anke Schmidt, Kristian Wende, Klaus-Dieter Weltmann, Thomas von Woedtke, Claus-Dieter Heidecke, Lars-Ivo Partecke and André Käding

Cancers 2019, 11(9), 1237; https://doi.org/10.3390/cancers11091237 - 23 Aug 2019

Cited by 43 | Viewed by 5580

Abstract

Cold physical plasma has limited tumor growth in many preclinical models and is, therefore, suggested as a putative therapeutic option against cancer. Yet, studies investigating the cells’ metastatic behavior following plasma treatment are scarce, although being of prime importance to evaluate the safety [...] Read more.

Cold physical plasma has limited tumor growth in many preclinical models and is, therefore, suggested as a putative therapeutic option against cancer. Yet, studies investigating the cells’ metastatic behavior following plasma treatment are scarce, although being of prime importance to evaluate the safety of this technology. Therefore, we investigated four human pancreatic cancer cell lines for their metastatic behavior in vitro and in chicken embryos (in ovo). Pancreatic cancer was chosen as it is particularly metastatic to the peritoneum and systemically, which is most predictive for outcome. In vitro, treatment with the kINPen plasma jet reduced pancreatic cancer cell activity and viability, along with unchanged or decreased motility. Additionally, the expression of adhesion markers relevant for metastasis was down-regulated, except for increased CD49d. Analysis of 3D tumor spheroid outgrowth showed a lack of plasma-spurred metastatic behavior. Finally, analysis of tumor tissue grown on chicken embryos validated the absence of an increase of metabolically active cells physically or chemically detached with plasma treatment. We conclude that plasma treatment is a safe and promising therapeutic option and that it does not promote metastatic behavior in pancreatic cancer cells in vitro and in ovo. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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Review

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19 pages, 1039 KiB

Open AccessReview

Molecular Mechanisms of the Efficacy of Cold Atmospheric Pressure Plasma (CAP) in Cancer Treatment

by Marie Luise Semmler, Sander Bekeschus, Mirijam Schäfer, Thoralf Bernhardt, Tobias Fischer, Katharina Witzke, Christian Seebauer, Henrike Rebl, Eberhard Grambow, Brigitte Vollmar, J. Barbara Nebe, Hans-Robert Metelmann, Thomas von Woedtke, Steffen Emmert and Lars Boeckmann

Cancers 2020, 12(2), 269; https://doi.org/10.3390/cancers12020269 - 22 Jan 2020

Cited by 142 | Viewed by 9066

Abstract

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in [...] Read more.

Recently, the potential use of cold atmospheric pressure plasma (CAP) in cancer treatment has gained increasing interest. Especially the enhanced selective killing of tumor cells compared to normal cells has prompted researchers to elucidate the molecular mechanisms for the efficacy of CAP in cancer treatment. This review summarizes the current understanding of how CAP triggers intracellular pathways that induce growth inhibition or cell death. We discuss what factors may contribute to the potential selectivity of CAP towards cancer cells compared to their non-malignant counterparts. Furthermore, the potential of CAP to trigger an immune response is briefly discussed. Finally, this overview demonstrates how these concepts bear first fruits in clinical applications applying CAP treatment in head and neck squamous cell cancer as well as actinic keratosis. Although significant progress towards understanding the underlying mechanisms regarding the efficacy of CAP in cancer treatment has been made, much still needs to be done with respect to different treatment conditions and comparison of malignant and non-malignant cells of the same cell type and same donor. Furthermore, clinical pilot studies and the assessment of systemic effects will be of tremendous importance towards bringing this innovative technology into clinical practice. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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34 pages, 2618 KiB

Open AccessReview

Modifying the Tumour Microenvironment: Challenges and Future Perspectives for Anticancer Plasma Treatments

by Angela Privat-Maldonado, Charlotta Bengtson, Jamoliddin Razzokov, Evelien Smits and Annemie Bogaerts

Cancers 2019, 11(12), 1920; https://doi.org/10.3390/cancers11121920 - 2 Dec 2019

Cited by 59 | Viewed by 5646

Abstract

Tumours are complex systems formed by cellular (malignant, immune, and endothelial cells, fibroblasts) and acellular components (extracellular matrix (ECM) constituents and secreted factors). A close interplay between these factors, collectively called the tumour microenvironment, is required to respond appropriately to external cues and [...] Read more.

Tumours are complex systems formed by cellular (malignant, immune, and endothelial cells, fibroblasts) and acellular components (extracellular matrix (ECM) constituents and secreted factors). A close interplay between these factors, collectively called the tumour microenvironment, is required to respond appropriately to external cues and to determine the treatment outcome. Cold plasma (here referred as ‘plasma’) is an emerging anticancer technology that generates a unique cocktail of reactive oxygen and nitrogen species to eliminate cancerous cells via multiple mechanisms of action. While plasma is currently regarded as a local therapy, it can also modulate the mechanisms of cell-to-cell and cell-to-ECM communication, which could facilitate the propagation of its effect in tissue and distant sites. However, it is still largely unknown how the physical interactions occurring between cells and/or the ECM in the tumour microenvironment affect the plasma therapy outcome. In this review, we discuss the effect of plasma on cell-to-cell and cell-to-ECM communication in the context of the tumour microenvironment and suggest new avenues of research to advance our knowledge in the field. Furthermore, we revise the relevant state-of-the-art in three-dimensional in vitro models that could be used to analyse cell-to-cell and cell-to-ECM communication and further strengthen our understanding of the effect of plasma in solid tumours. Full article

(This article belongs to the Special Issue Plasma in Cancer Treatment)

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