# Medical Gas Plasma Treatment in Head and Neck Cancer--Challenges and Opportunities
## 3 HNSCC and Oxidative Stress  
The results of numerous investigations indicate a crucial role of physical plasma-generated reactive oxygen and nitrogen species (ROS) for the inhibitory and antitumoral activity on cancer cells observed with plasma treatment [58]. ROS seem to be important since they trigger the biochemistry and redox signaling pathways necessary to promote oxidation-related changes that lead to altered cellular functions and the activation of apoptosis [30; 59]. This is because it is known that ROS are biologically active components that modulate cellular responses in targeted cells [60]. Direct plasma treatment primarily influences the cell physiology through the presence of highly active, short-lived ROS like OH, O\({}_{2}\)-, NO, and HOONO, whereas indirect treatment with plasma-conditioned liquid exhibits toxic cell effects, primarily due to long-lived species like H\({}_{2}\)O\({}_{2}\), NO\({}_{2}\)-, and NO\({}_{3}\)-[61]. The impact of both plasma-type-generated ROS has been described mainly for the treatment of head and neck squamous cell carcinoma cells. [PERSON] et al. showed the ROS-mediated inactivation of plasma-treated head and neck cancer cells could be rescued via the addition of antioxidants, which abolished plasma-mediated cytotoxicity through the reduction of apoptosis, levels of intracellular ROS, mitochondrial superoxide, and the loss of mitochondrial membrane potential (MMP) [32]. Besides the initiation of cell deathmechanisms, ROS cause the general elevation of oxidative stress within cancer cells [26]. These ROS or secondary ROS may be able to alter cellular structures, such as DNA and RNA, and proteins could be damaged, potentially leading to autophagy and induction of the DNA-damage response. The latter may be a consequence of the DNA secondary double-strand breaks that have been suggested as a consequence of plasma treatment of head and neck cancer cells [34], but this finding is likely attributed to apoptosis induction [62]. Furthermore, cancer cells might be more prone toward ROS than non-malignant cells since they often display a decreased antioxidant capacity, resulting in higher susceptibility toward ROS-induced signaling responses and cell death [20].  
Relating to head and neck cancer, physical plasma-generated ROS have an additional advantage. They inhibit and decrease the microbial growth on advanced-stage tumors, which generally is an issue because the contamination of the tissue produces a hostile odor that negatively affects social interactions and reduces the patients' quality of life [21]. Here, the antimicrobial efficacy of plasma [63] aids in the palliation of the patients. Besides cold physical plasma, other therapy approaches aim for ROS generation to target cancer selectively based on the different redox states of non-malignant and malignant cells. Since malignant cells possess elevated intrinsic ROS generation, they are more dependent on antioxidants for cell survival; therefore, they are more vulnerable to further oxidative stress [20]. The chemotherapeutic agent cisplatin has been used widely in the treatment of head and neck cancer, mostly in combination with other anticancer drugs like docetaxel, fluorouracil (5 FU), or 2-deoxy-d-glucose, whereby they produce intracellular ROS and oxidative stress [64; 65]. These ROS lead to a shift in the cellular antioxidant defense capacity and the MMP, which initiates anti-proliferative effects and apoptosis in cancer cells [30].