Non-thermal plasma specifically kills oral squamous cell carcinoma cells in a catalytic Fe(II)-dependent manner

Abstract

Oral cancer accounts for ~2% of all cancers worldwide, and ther apeutic intervention is closely associated with quality of life. Here, we evaluated the effects of non thermal plasma on oral squa mous cell carcinoma cells with special reference to catalytic Fe(II). Non thermal plasma exerted a specific killing effect on oral squa mous cell carcinoma cells in comparison to fibroblasts. Furthermore, the effect was dependent on the amounts of catalytic Fe(II), pres ent especially in lysosomes. After non thermal plasma application, lipid peroxidation occurred and peroxides and mitochondrial super oxide were generated. Cancer cell death by non thermal plasma was promoted dose dependently by prior application of ferric ammonium citrate and prevented by desferrioxamine, suggesting the association of ferroptosis. Potential involvement of apoptosis was also observed with positive terminal deoxynucleaotidyl transferase mediated dUTP nick end labeling and annexin V results. Non thermal plasma exposure significantly suppressed the migratory, invasive and colony forming abilities of squamous cell carcinoma cells. The oral cavity is easily observable; therefore, non thermal plasma can be directly applied to the oral cavity to kill oral squamous cell carcinoma without damaging fibroblasts. In conclusion, non thermal plasma treatment is a potential therapeutic option for oral cancer.

Medical Gas Plasma Treatment in Head and Neck Cancer—Challenges and Opportunities

“…In vitro SCC15 Shi et al [23] Inactivation effect of plasma-derived active species on oral cancer cells is higher through a small amount of medium than through a high amount of medium. Sato et al [27] Plasma-treatment induced cell death of head and neck squamous cell carcinoma cells due to increased gene expression of mitochondrial E3 ubiquitin-protein ligase 1 (MUL1), which inhibited the level of AKT and p-AKT. Plasma-conditioned liquid inhibited tumor progression by increasing the MUL1 level and reducing p-AKT levels in in vivo head and neck tumor models.…”

“…Most of these experimental in vitro studies used the oral squamous cell carcinoma cell line SCC-15, as well as SCC-25, and highlighted their plasma-induced inactivation due to the reduction of cell growth, induction of apoptosis, and secondary DNA damage, especially through plasma-derived ROS [19,25,28,[34][35][36][37][38]. Other HNSCC cell lines were also tested, showing one or more of the tumor-toxic plasma-associated characteristics [6,19,22,24,[26][27][28][29][30][31][32][33]37]. In addition, HNSCC has been shown to be more prone to physical plasma treatment than non-malignant cells since the viability of the latter did not significantly decrease after plasma application.…”

“…In addition, HNSCC has been shown to be more prone to physical plasma treatment than non-malignant cells since the viability of the latter did not significantly decrease after plasma application. The fact that plasma selectively targets cancer cells, leaving non-malignant cell types, such as human fibroblasts (e.g., human gingival fibroblast-1 (HGF-1), HS-K, and IMR-SV-90) or human keratinocytes (HaCaT) unaffected, makes plasma a promising tool for adjuvant head and neck cancer therapy [25,27,29]. Moreover, two studies demonstrated an enhanced selectivity of plasma after the addition of antibody-conjugated gold nanoparticles, which specifically targeted SCC-25 head and neck cancer cells [35,36].…”

“…Furthermore, physical-plasma-induced ROS selectively enhances the iron-dependent lipid peroxidation and mitochondrial superoxide formation in HNSCC cells since they harbor more catalytic Fe(II) than non-malignant cells. Consequently, the amount of catalytic Fe(II) matters for the killing efficacy of physical plasma, suggesting the presence of ferroptosis processes during cancer cell inactivation [27]. Besides inactivation, several studies also point to a decrease in the motility of squamous cell carcinoma cells after plasma treatment [6].…”

“…Kang et al revealed that the migration and invasion of the head and neck cancer cell lines MSKQLL1 and SCC1483 were significantly reduced after plasma treatment through the downregulated expression of the focal adhesion kinase (FAK), integrin, and paxillin, especially when utilizing N 2 as a feed gas [31]. The ability to form colonies was also impaired by plasma treatment in various HNSCC cell lines [19,27,30]. The fact that the application of different feed gases influences the effectivity of plasma, as shown by Kang et al, demonstrates the possibility to optimize physical plasma further for head and neck cancer treatment [31].…”