Abstract 1388: Non-thermal plasma-activated medium induces ferroptotic cell death by intracellular ferrous iron overload in head and neck cancer

Abstract The notoriously high proliferation rate of cancer cells requires them to constantly deal with the balance adjustment between oxidative stress overload and upregulated protective antioxidant pathways. It puts them in a vulnerable state whenever one piece of this puzzle went out of control. Non-thermal plasma (NTP) is partially ionized gas operated at or around body temperature and has emerged as a new potential anti-cancer therapy due to its ability to release and induce ROS, RNS, and other free radicals as well as generate UV- photon and electromagnetic field; but the specific mechanism and its specificity to cancer cell are still controversial. Using transcriptomic analysis, we previously reported the link between NTP-activated media (NTPAM)and apoptosis; but the sequencing data also revealed a strong Ferroptotic response in all the 6Head and Neck cancer cell lines we checked. Ferroptosis is a newly identified oxidative-regulated cell death, characterized by the iron-dependent generation of lipid peroxidation. In this study, we found the prolonged treatment of NTPAM-induced cell death via the non-canonical ferroptosis pathway by directly increasing intracellular toxic ferrous Iron (Fe2+). We found that the excessive overexpression of HMOX1 under prolonged NTPAM-induced oxidative stress was actually responsible for the surge of intracellular Fe2+ due to the increase of heme degradation. Pharmacological inhibition or RNA silencing of HMOX1 was able to rescue 2 HNC cell lines from NTPAM-induced increased Iron concentration as well as ferroptosis cell death, both in vivo and in vitro. These results suggest NTP directly induces ferroptosis via an increase of Fe2+ concentration by triggering the over-responding of the NRF2 - HMOX1 antioxidant system. This finding could be exploited to develop future NTP-based cancer therapy as well as in combination with other Iron sensitive anti-neoplastic agents; and could be a potential method of overcoming conventional cancer treatment resistance. Citation Format: QuocKhanh Nguyen, Chan Oh, Seung-Nam Jung, Yudan Piao, Mi Ae Lim, Young Il Kim, Yanli Jin, Hae Jong Kim, Bon Seok Koo. Non-thermal plasma-activated medium induces ferroptotic cell death by intracellular ferrous iron overload in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1388.