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Cancer stem cells (CSCs) represent a small subset of slowly dividing cells with tumor-initiating ability. They can self-renew and differentiate into all the distinct cell populations within a tumor. CSCs are naturally resistant to chemotherapy or radiotherapy. CSCs, thus, can repopulate a tumor after therapy and are responsible for recurrence of disease. Stemness manifests itself through, among other things, the expression of stem cell markers, the ability to induce sphere formation and tumor growth in vivo, and resistance to chemotherapeutics and irradiation. Stemness is maintained by keeping levels of reactive oxygen species (ROS) low, which is achieved by enhanced activity of antioxidant pathways. Here, cellular sources of ROS, antioxidant pathways employed by CSCs, and underlying mechanisms to overcome resistance are discussed.
An Serin139 phosphoryliertes gamma Histon H2A.X (γH2A.X) hat sich über die Jahrzehnte als sensitiver Surrogat-Endpunkt Strahlen-induzierter DNA-Schäden, insbesondere von DNA-Doppelstrangbrüchen (DSBs) etabliert. Daher wurde γH2A.X in seiner biomedizinischen Anwendung als geeigneter Marker und genereller Indikator direkter DNA-Schäden anderer Agenzien, beispielsweise niedrig konzentrierter primär exogener reaktiver Sauerstoffspezies (ROS), deren intrazelluläre Effekte weniger direkt auf eine DNA-Oxidation oder das Einfügen von Strangbrüchen abzielen, angesehen. Nicht-thermisches physikalisches Plasma (NTPP), ein teilweise ionisiertes Gas, dessen biochemische Wirkung in vitro hauptsächlich über Freisetzung reaktiver Sauerstoff- und Stickstoffspezies (RONS) in der flüssigen Phase der Zellumgebung vermittelt wird, setzt lebende Systeme dosisabhängig oxidativem Stress aus und wird therapeutisch in der Wundbehandlung sowie Krebsbehandlung angewendet. Die γH2A.X Quantifizierung wurde häufig zur Beurteilung der Genotoxizität in Plasma-behandelten Zellen verwendet, wobei die NTPP-Exposition in vitro bereits häufig einen γH2A.X Anstieg zeigte, was zu der Hypothese führte, dass ein (oxidativer) DNA-Schaden die direkte Konsequenz Plasma-generierter ROS sei. Darüber hinaus tritt γH2A.X auch während der Apoptose auf, die wiederum selbst mit der NTPP- und ROS-Exposition assoziiert ist. Die vorliegende Arbeit untersuchte die γH2A.X-Induktion in einer Lymphoblasten-Zelllinie bei ROS-Exposition (NTPP, H2O2 oder HOCl) bzw. Behandlung mit UVB-Licht. Durch Verwendung von Antioxidantien wurden sowohl die Zytotoxizität als auch die γH2A.X-Induktion bei allen Arten der ROS-Quellen außer bei UVB-Strahlung aufgehoben. Inhibition der Signalwege für oxidativen Stress (p38-MAPK) und Apoptose (Pan-Caspase) hemmten signifikant die γH2A.X-Induktion bei ROS, jedoch nicht bei UVB-Licht. Letztlich und trotz H2A.X Phosphorylierung führte die UVB-Licht- und eben nicht die NTPP-Exposition zu einer signifikanten Bildung von Mikronuklei (MN), die einen funktionellen Endpunkt genotoxischer DSBs darstellen, sodass trotz der γH2A.X Präsenz kein nachhaltiges mutagenes Potential der medizinischen Plasmabehandlung identifiziert werden konnte. Im Gegensatz zu Strahlen- oder Chemotherapeutika- induziertem und somit DNA-Schaden-assoziiertem γH2A.X zeigen die Daten dieser Arbeit die H2A.X Phosphorylierung weniger als Folge eines ROS-vermittelten primären DNA-Schadens, sondern vielmehr im Licht redox-sensitiver Signalwege der Apoptose, sodass künftige γH2A.X Messungen im medizinischen Bereich, insbesondere in der Plasmamedizin und Redoxbiologie einer sorgfältigen Interpretation bedürfen.
Despite continuous advances in therapy, malignant melanoma is still among the deadliest
types of cancer. At the same time, owing to its high plasticity and immunogenicity, melanoma is
regarded as a model tumor entity when testing new treatment approaches. Cold physical plasma is a
novel anticancer tool that utilizes a plethora of reactive oxygen species (ROS) being deposited on the
target cells and tissues. To test whether plasma treatment would enhance the toxicity of an established
antitumor therapy, ionizing radiation, we combined both physical treatment modalities targeting
B16F10 murine melanoma cell in vitro. Repeated rather than single radiotherapy, in combination
with gas plasma-introduced ROS, induced apoptosis and cell cycle arrest in an additive fashion. In
tendency, gas plasma treatment sensitized the cells to subsequent radiotherapy rather than the other
way around. This was concomitant with increased levels of TNFα, IL6, and GM-CSF in supernatants.
Murine JAWS dendritic cells cultured in these supernatants showed an increased expression of cell
surface activation markers, such as MHCII and CD83. For PD-L1 and PD-L2, increased expression
was observed. Our results are the first to suggest an additive therapeutic effect of gas plasma and
radiotherapy, and translational tumor models are needed to develop this concept further.
Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen
species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and
recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with
an immunological dimension, successful antigen presentation and inflammation modulation is a
key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However,
the inflammatory consequences of DCs following plasma exposure are unknown. To this end,
human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes;
exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles
were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used.
Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable
increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell
costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether,
this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in
human moDCs, which might exert beneficial effects in the tumor microenvironment.
Reactive oxygen species (ROS) have been subject of increasing interest in the pathophysiology and therapy of cancers in recent years. In skin cancer, ROS are involved in UV-induced tumorigenesis and its targeted treatment via, e.g., photodynamic therapy. Another recent technology for topical ROS generation is cold physical plasma, a partially ionized gas expelling dozens of reactive species onto its treatment target. Gas plasma technology is accredited for its wound-healing abilities in Europe, and current clinical evidence suggests that it may have beneficial effects against actinic keratosis. Since the concept of hormesis dictates that low ROS levels perform signaling functions, while high ROS levels cause damage, we investigated herein the antitumor activity of gas plasma in non-melanoma skin cancer. In vitro, gas plasma exposure diminished the metabolic activity, preferentially in squamous cell carcinoma cell (SCC) lines compared to non-malignant HaCaT cells. In patient-derived basal cell carcinoma (BCC) and SCC samples treated with gas plasma ex vivo, increased apoptosis was found in both cancer types. Moreover, the immunomodulatory actions of gas plasma treatment were found affecting, e.g., the expression of CD86 and the number of regulatory T-cells. The supernatants of these ex vivo cultured tumors were quantitatively screened for cytokines, chemokines, and growth factors, identifying CCL5 and GM-CSF, molecules associated with skin cancer metastasis, to be markedly decreased. These findings suggest gas plasma treatment to be an interesting future technology for non-melanoma skin cancer topical therapy.
Medical gas plasmas are of emerging interest in pre-clinical oncological research. Similar to an array of first-line chemotherapeutics and physics-based therapies already approved for clinical application, plasmas target the tumor redox state by generating a variety of highly reactive species eligible for local tumor treatments. Considering internal tumors with limited accessibility, medical gas plasmas help to enrich liquids with stable, low-dose oxidants ideal for intratumoral injection and lavage. Pre-clinical investigation of such liquids in numerous tumor entities and models in vitro and in vivo provided evidence of their clinical relevance, broadening the range of patients that could benefit from medical gas plasma therapy in the future. Likewise, the application of such liquids might be promising for recurrent BRAF(V600E) papillary thyroid carcinomas, resistant to adjuvant administration of radioiodine. From a redox biology point of view, studying redox-based approaches in thyroid carcinomas is particularly interesting, as they evolve in a highly oxidative environment requiring the capability to cope with large amounts of ROS/RNS. Knowledge on their behavior under different redox conditions is scarce. The present study aimed to clarify resistance, proliferative activity, and the oxidative stress response of human papillary thyroid cancer cells K1 after exposure to plasma-oxidized DMEM (oxDMEM). Cellular responses were also evaluated when treated with different dosages of hydrogen peroxide and the RNS donor sodium nitroprusside (SNP). Our findings outline plasma-oxidized liquids as a promising approach targeting BRAF(V600E) papillary thyroid carcinomas and extend current knowledge on the susceptibility of cells to undergo ROS/RNS-induced cell death.
Reactive species generated by medical gas plasma technology can be enriched in liquids for use in oncology targeting disseminated malignancies, such as metastatic colorectal cancer. Notwithstanding, reactive species quantities depend on the treatment mode, and we recently showed gas plasma exposure in conductive modes to be superior for cancer tissue treatment. However, evidence is lacking that such a conductive mode also equips gas plasma-treated liquids to confer augmented intraperitoneal anticancer activity. To this end, employing atmospheric pressure argon plasma jet kINPen-treated Ringer’s lactate (oxRilac) in a CT26-model of colorectal peritoneal carcinomatosis, we tested repeated intraabdominal injection of such remotely or conductively oxidized liquid for antitumor control and immunomodulation. Enhanced reactive species formation in conductive mode correlated with reduced tumor burden in vivo, emphasizing the advantage of conduction over the free mode for plasma-conditioned liquids. Interestingly, the infiltration of lymphocytes into the tumors was equally enhanced by both treatments. However, significantly lower levels of interleukin (IL)4 and IL13 and increased levels of IL2 argue for a shift in intratumoral T-helper cell subpopulations correlating with disease control. In conclusion, our data argue for using conductively over remotely prepared plasma-treated liquids for anticancer treatment.
Cold medical gas plasmas are under pre-clinical investigation concerning their hemostatic activity and could be applied for intra-operative bleeding control in the future. The technological leap innovation was their generation at body temperature, thereby causing no thermal harm to the tissue and ensuring tissue integrity. This directly contrasts with current techniques such as electrocautery, which induces hemostasis by carbonizing the tissue using a heated electrode. However, the necrotized tissue is prone to fall, raising the risk of post-operative complications such as secondary bleedings or infection. In recent years, various studies have reported on the ability of medical gas plasmas to induce blood coagulation, including several suggestions concerning their mode of action. As non-invasive and gentle hemostatic agents, medical gas plasmas could be particularly eligible for vulnerable tissues, e.g., colorectal surgery and neurosurgery. Further, their usage could be beneficial regarding the prevention of post-operative bleedings due to the absence or sloughing of eschar. However, no clinical trials or individual healing attempts for medical gas plasmas have been reported to pave the way for clinical approvement until now, despite promising results in experimental animal models. In this light, the present mini-review aims to emphasize the potential of medical gas plasmas to serve as a hemostatic agent in clinical procedures. Providing a detailed overview of the current state of knowledge, feasible application fields are discussed, and possible obstacles are addressed.
Heat Shock Protein 27 Affects Myeloid Cell Activation and Interaction with Prostate Cancer Cells
(2022)
Heat shock proteins are cytoprotective molecules induced by environmental stresses. The small heat shock protein 27 (Hsp27) is highly expressed under oxidative stress conditions, mediating anti-oxidative effects and blocking apoptosis. Since medical gas plasma treatment subjects cancer cells to a multitude of reactive oxygen species (ROS), inducing apoptosis and immunomodulation, probable effects of Hsp27 should be investigated. To this end, we quantified the extracellular Hsp27 in two prostate cancer cell lines (LNCaP, PC-3) after gas plasma-induced oxidative stress, showing a significantly enhanced release. To investigate immunomodulatory effects, two myeloid cell lines (THP-1 and HL-60) were also exposed to Hsp27. Only negligible effects on viability, intracellular oxidative milieu, and secretion profiles of the myeloid cells were found when cultured alone. Interestingly, prostate cancer-myeloid cell co-cultures showed altered secretion profiles with a significant decrease in vascular endothelial growth factor (VEGF) release. Furthermore, the myeloid surface marker profiles were changed, indicating an enhanced differentiation in co-culture upon Hsp27 treatment. Finally, we investigated morphological changes, proliferation, and interaction with prostate cancer cells, and found significant alterations in the myeloid cells, supporting the tendency to differentiate. Collectively, our results suggest an ambiguous effect of Hsp27 on myeloid cells in the presence of prostate cancer cells which needs to be further investigated.
AbstractCold physical plasma is a partially ionized gas that generates various components identified as potential anticancer compounds. Due to its topical application, cold plasmas are suitable, especially in dermatological applications. We, therefore, tested the cold plasma effects in skin cancer cells in vitro. An atmospheric pressure argon plasma jet was used as the plasma source. The plasma exposure alone reduced the metabolic activity and induced lethal effects in a treatment time-dependent fashion in both cell lines investigated. This was accompanied by executioner caspases 3 and 7, cleavage indicative of apoptosis and reduced cell migration and proliferation. Recent research also indicated roles of novel indirubin derivatives with potent anticancer effects. Three candidates were tested, and reduced metabolic activity and viability in a dose-dependent manner were found. Strikingly, one compound exerted notable synergistic toxicity when combined with plasma in skin cancer cells, which may be promising for future in vivo experiments.