Abstract
Nonthermal plasma (NTP) is generated by ionization of neutral gas molecules, which results in a mixture of energy particles including electrons and ions. Recent progress in the understanding of NTP has led to its application in the treatment of various diseases, including cancer. However, the molecular mechanisms of NTP-induced cell death are unclear. The purpose of this study was to evaluate the molecular mechanism of NTP in the induction of apoptosis of head and neck cancer (HNC) cells. The effects of NTP on apoptosis were investigated using MTT, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, Annexin V assays, and western blot analysis. The cells were examined for production of reactive oxygen species (ROS) using DCFCA or MitoSOX staining, intracellular signaling, and an animal model. NTP reduced HNC cell viability in a dose-dependent manner and induced apoptosis. NTP resulted in alteration of mitochondrial membrane potential and accumulation of intracellular ROS generated from the mitochondria in HNC cells. Blockade of ROS production by N-acetyl-L-cysteine inhibited NTP-induced apoptosis. NTP led to the phosphorylation of c-JUN N-terminal kinase (JNK) and p38, but not extracellular-regulated kinase. Treatment with JNK and p38 inhibitors alleviated NTP-induced apoptosis via ROS generation. Taken together, these results show that NTP induced apoptosis of HNC cells by a mechanism involving MAPK-dependent mitochondrial ROS. NTP inhibited the growth of pre-established FaDu tumors in a nude mouse xenograft model and resulted in accumulation of intracellular ROS. In conclusion, NTP induced apoptosis in HNC cells through a novel mechanism involving MAPK-mediated mitochondrial ROS. These findings show the therapeutic potential of NTP in HNC.
Highlights
Nonthermal plasma (NTP) is being investigated in terms of its biomedical application and has recently emerged as a novel tool in cancer treatment
We investigated whether NTP in Head and neck cancer (HNC) cells causes reactive oxygen species (ROS)-induced apoptosis, along with the molecular signals involved
NTP treatment of FaDu cells (2 kV for 1 s (15.7%) and 4 kV for 1 s (29.1%)) resulted in a significant increase in apoptosis compared with the control (5.1%) and gas-only (7.8%) groups (Figure 1b)
Summary
Nonthermal plasma (NTP) is being investigated in terms of its biomedical application and has recently emerged as a novel tool in cancer treatment. Acting as primary coordinators of the apoptotic processes, reactive oxygen species (ROS) generated by NTP can mediate apoptosis of mammalian cancer cells by mitochondrial dysfunction.[7,8] Free radicals have important roles in a number of biological processes and have been implicated in cellular redox signaling. Excessive amounts of free radicals secondary to an imbalance of the redox milieu can lead to cell damage and death.[9] It has been increasingly reported that DNA damage and reactive species generated by NTP could be the main causes of apoptosis in various types of cancer.[4,5,10,11]. We investigated whether NTP in HNC cells causes ROS-induced apoptosis, along with the molecular signals involved
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