Abstract
Cold physical plasma is a partially ionized gas investigated as a new anticancer tool in selectively targeting cancer cells in monotherapy or in combination with therapeutic agents. Here, we investigated the intrinsic resistance mechanisms of tumor cells towards physical plasma treatment. When analyzing the dose-response relationship to cold plasma-derived oxidants in 11 human cancer cell lines, we identified four ‘resistant’ and seven ‘sensitive’ cell lines. We observed stable intracellular glutathione levels following plasma treatment only in the ‘resistant’ cell lines indicative of altered antioxidant mechanisms. Assessment of proteins involved in GSH metabolism revealed cystine-glutamate antiporter xCT (SLC7A11) to be significantly more abundant in the ‘resistant’ cell lines as compared to ‘sensitive’ cell lines. This decisive role of xCT was confirmed by pharmacological and genetic inhibition, followed by cold physical plasma treatment. Finally, microscopy analysis of ex vivo plasma-treated human melanoma punch biopsies suggested a correlation between apoptosis and basal xCT protein abundance. Taken together, our results demonstrate that xCT holds the potential as a biomarker predicting the sensitivity of tumor cells towards plasma treatment.
Highlights
Among many types of solid tumors, breast, colorectal, lung, and prostate account for about 60% of all cancer cases in the western world
To test the cytotoxicity of cold physical plasma, 11 different tumor cell lines were exposed to increasing plasma treatment times (30s, 60s, 120 s) and cultured for 24 h thereafter
There was no significant difference in the basal GSH or the GSH/GSSH ratio between the ‘sensitive’ and ‘resistant’ cell lines
Summary
Among many types of solid tumors, breast, colorectal, lung, and prostate account for about 60% of all cancer cases in the western world. A majority of existing strategies (e.g., radiotherapy, chemotherapy, and small molecule therapy) targeting tumor cells eventually induce oxidative stress and cell death. Cold physical plasma is an emerging treatment strategy, which employs unique RONS (reactive oxygen and nitrogen species) to selectively target tumor cells by perturbing cellular redox balance leading to oxidative stress, mitochondrial dysfunction, and cell death. The advantage of this strategy is that it can directly transfer RONS to the tumor tissue without the need for any systemic agents. Tumors are extraordinarily heterogeneous, and treatment responses are determined frequently by the cellular origin and mutational load
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