Abstract
Cold atmospheric plasma (CAP) that generates reactive oxygen species (ROS) has received considerable scientific attentions as a new type of anticancer. In particular, an indirect treatment method of inducing cancer cell death through plasma-activated medium (PAM), rather than direct plasma treatment has been well established. Although various cell death pathways such as apoptosis, necroptosis, and autophagy have been suggested to be involved in PAM-induced cell death, the involvement of ferroptosis, another type of cell death regulated by lipid ROS is largely unknown. This study reports, that PAM promotes cell death via ferroptosis in human lung cancer cells, and PAM increases intracellular and lipid ROS, thereby resulting in mitochondrial dysfunction. The treatment of cells with N-acetylcysteine, an ROS scavenging agent, or ferrostatin-1, a ferroptosis inhibitor, protects cells against PAM-induced cell death. Interestingly, ferroptosis suppressor protein 1 (FSP1) is downregulated upon PAM treatment. Furthermore, the treatment of cells with iFSP1, an inhibitor of FSP1, further enhances PAM-induced ferroptosis. Finally, this study demonstrates that PAM inhibits tumor growth in a xenograft model with an increase in 4-hydroxynoneal and PTGS2, a byproduct of lipid peroxidation, and a decrease in FSP1 expression. This study will provide new insights into the underlying mechanism and therapeutic strategies of PAM-mediated cancer treatment.
Highlights
Cold atmospheric plasma (CAP), an ionized gas generated at room temperature, contains neutral molecules and atoms, electrons, various types of ions, excited species, and radicals [1–3]
These results suggest that plasma-activated medium (PAM)-mediated reduction in ferroptosis suppressor protein 1 (FSP1) protein levels contributes to ferroptosis
In our previous study, we showed that CAP can generate various reactive oxygen and nitrogen species in the culture medium
Summary
Cold atmospheric plasma (CAP), an ionized gas generated at room temperature, contains neutral molecules and atoms, electrons, various types of ions, excited species, and radicals [1–3]. We reported that cancer cell death is induced through indirect treatment using a plasmaactivated medium (PAM), and PAM increases the intracellular ROS levels and regulates JNK/p53/Bax signaling, resulting in apoptosis [26–28]. Official journal of CDDpress mediated cell death In support of this hypothesis, we observed investigated whether oxidative stress-related genes changed with several characteristics of ferroptosis in PAM-induced cell death. We showed that PAM leads to changes in the levels of major altered expression of oxidative stress-related genes In both cell proteins involved in ferroptosis and the accumulation of labile iron lines, the gene expression of NCOA7 decreased by < 0.5-fold and lipid peroxidation, meeting the principal criterion for (Supplementary Table 1). When we co-treated the cells with NAC and PAM, intracellular ROS levels significantly decreased
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