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In a published in the journal Science Bulletin, researchers from the Nano Life Science Institute (WPI-NanoLSI) at Kanazawa University utilized hopping probe scanning ion conductance microscopy (HPICM) and highly sensitive platinum-functionalized nanoelectrodes to conduct an in-depth investigation of the dynamic response of individual living colorectal cancer Caco-2 cells to changes in intracellular and extracellular hydrogen peroxide (H₂O₂) gradients, specifically focusing on eustress, at the single-cell level and in real-time.

Their findings hold promise for innovative therapies against cancer and H₂O₂-related inflammatory diseases.

Reactive Oxygen Species (ROS) production plays a significant role in various diseases, including atherosclerosis, chronic obstructive pulmonary disease, and cancer. Despite promising preclinical antioxidant therapies, clinical trials have yielded unsatisfactory results. Hydrogen peroxide (H₂O₂), a stable ROS derivative, acts as a crucial participant in physiological signaling by serving as a eustressor.

The concentration of H₂O₂ in the tumor microenvironment is closely linked to the occurrence and progression of colorectal cancer. A deeper understanding of how H₂O₂ functions and its specific efficacy in individual cancer cells may pave the way for more effective ROS-related treatments.

The authors utilized hopping probe scanning ion conductivity microscopy (HPICM) alongside Pt-functionalized nanoelectrodes to quantitatively assess the dynamic response in cell morphology, cell mechanical properties, and extracellular to intracellular eustress H₂O₂ gradients of individual colorectal cancer Caco-2 cells under H₂O₂ eustress.

The investigation revealed that exposure to 0.1 or 1 mmol/L H₂O₂ eustress increased the extracellular to intracellular H₂O₂ gradient from 0.3 to 1.91 or 3.04, respectively. Additionally, the study found that F-actin-dependent cell stiffness increased under eustress of 0.1 mmol H₂O₂ but decreased under eustress of 1 mmol H₂O₂.

Furthermore, eustress-induced cell stiffness was positively regulated by AKT activation and negatively influenced the expression of the H₂O₂-scavenging enzyme GPX2, ultimately maintaining relatively stable cellular H₂O₂ levels.

This study suggests that the eustress induced by low levels of H₂O₂ may contribute to the failure of some H₂O₂ targeted therapies. The results uncover a novel interplay between cellular physical properties and biochemical signaling in cancer cells' antioxidant defense, shedding light on the utilization of H₂O₂ eustress for survival at the single-cell level.

This understanding is critical for comprehending cancer development and other H₂O₂-related inflammatory diseases. Inhibiting GPX under H₂O₂ eustress resulted in cytotoxicity, suggesting a potential enhancement for colon cancer treatment. These findings hold promise for the development of innovative therapies targeting cancer and H₂O₂-related inflammatory diseases.