Chronic oxidative stress adaptation in head and neck cancer cells generates slow-cyclers with decreased tumour growth in vivo

Abstract

Background Reactive oxygen species (ROS) are implicated in cancer therapy and as drivers of microenvironmental tumour cell adaptations. Medical gas plasma is a multi-ROS generating technology that has been shown effective for palliative tumour control in head and neck cancer (HNC) patients before tumour cells adapted to the oxidative stress and growth regressed fatally. Methods In a bedside-to-bench approach, we sought to explore the oxidative stress adaptation in two human squamous cell carcinoma cell lines. Gas plasma was utilised as a putative therapeutic agent and chronic oxidative stress inducer. Results Cellular responses of single and multiple treated cells were compared regarding sensitivity, cellular senescence, redox state and cytokine release. Whole transcriptome analysis revealed a strong correlation of cancer cell adaption with increased interleukin 1 receptor type 2 (IL1R2) expression. Using magnetic resonance imaging, tumour growth and gas plasma treatment responses of wild-type (WT) and repeatedly exposed (RE) A431 cells were further investigated in a xenograft model in vivo. RE cells generated significantly smaller tumours with suppressed inflammatory secretion profiles and increased epidermal growth factor receptor (EGFR) activity showing significantly lower gas plasma sensitivity until day 8. Conclusions Clinically, combination treatments together with cetuximab, an EGFR inhibitor, may overcome acquired oxidative stress resistance in HNC.

Interactions between oxidative stress and senescence in cancer: Mechanisms, therapeutic implications, and future perspectives

“…The consistent outcome identified that senescence in cancer cells depressed the progression of cancer in an opposing manner. In head and neck cancer, gas plasma treatment induced cellular senescence in cancer cells through the accumulation of oxidative stress, attenuating the proliferation of cancer cells in vivo [ 62 ]. LincRNA-p21 upregulated by 1-methyl-4-phenylpyridinium could induce oxidative stress to enhance neuroblastoma cell senescence by suppressing the Wnt/β-catenin pathway, deducing the proliferation and viability of tumor cell [ 63 ].…”

Medical gas plasma technology: Roadmap on cancer treatment and immunotherapy

“…In these situations, frequently repeated gas plasma exposure is amendable to control, for instance, tumor infections and/or growth to support palliation, and potentially also provide immuno-stimulation. In the clinic, however, head and neck cancer cell adaptation to gas plasma therapy-induced tumor toxicity was also observed [ 221 ], and frequent gas plasma-induced oxidative stress can select for slow-cycling tumor cells with improved stress resistance [ 292 ]. Such adaptation and reduced therapy responses, however, has been observed for most cancer therapies utilized in the clinic, and are not specific to gas plasma therapy per se .…”

Effects and Mechanisms of Non-Thermal Plasma-Mediated ROS and Its Applications in Animal Husbandry and Biomedicine

“…In addition, it has been found that NTP-induced repetitive oxidative stress situations contribute to identifying potential targets for overcoming anti-cancer drug resistance [144]. However, the above studies still have some limitations, especially the short-life and weak penetration of ROS, which limit the widespread application of NTP in cancer therapy.…”