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

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 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.

Keywords: cold physical plasma; plasma medicine; reactive oxygen and nitrogen species.

Figure 1

Overview of the current understanding of molecular mechanisms involved in the efficacy of cold atmospheric pressure plasma (CAP) in cancer treatment ① Aquaporins (AQ), often increased in cancer cells, facilitate transition of reactive oxygen and nitrogen species (RONS) into the cell, while minimal amounts may also diffuse through the cell membrane. ② Lipid peroxidation by free radicals leads to pore formation in the membrane and hence facilitates diffusion of reactive species into the cell. This effect may be enhanced in cancer cells due to reduced levels of cholesterol-a lipid important for providing membrane stability and fluidity. ③ Increased intracellular RONS interfere with calcium signaling (e.g., through interaction with inositol trisphosphate receptor [IP3-RR] and ryanoid receptor [RR]) resulting in increased calcium influx into cytosol. ④ Furthermore, RONS induced endoplasmic reticulum (ER) stress leads to a calcium influx into mitochondria reducing the membrane potential and hence inducing mitochondria-dependent apoptosis. ⑤ CAP induced DNA double strand breaks (DSB) cause a DNA damage response including activation of ATM, H2AX, p53, and p73. These DSB may not be a direct effect of CAP on DNA but rather a consequence of CAP induced apoptosis. ⑥ Increased levels of RONS produced by CAP overwhelm the antioxidant system and hence limit its protective effect against oxidative stress. ⑦ Reduced expression of integins after CAP treatment may explain the reduction of adhesion, migration, and invasion after CAP treatment. ⑧ As a consequence of CAP treatment necrosis, apoptosis, and senescence have been reported. Which of these processes is induced seems to be dose-dependent. However, the underlying mechanisms that decide which process of growth arrest or cell death as a consequence of CAP treatment is triggered still need to be further elucidated. MAM = mitochondria-associated ER membranes.