Abstract
Tumor hypoxia is the principal cause of clinical radioresistance. Despite its established role as radiosensitizer, hydrogen peroxide (H2O2) encounters clinical limitations due to stability and toxicity concerns. Recent advancements in drug delivery combine H2O2 with sodium hyaluronate (SH), enabling intratumoral administration of H2O2. This study investigates the radiomodulatory pathways of Kochi Oxydol-Radiation for Unresectable Carcinomas (KORTUC) (H2O2+SH) under hypoxia. CT26 and 4T1 tumor cells were exposed to H2O2, SH and KORTUC under hypoxic conditions. Toxicity levels were determined using MTT and live-cell analysis. KORTUC's radiomodulatory properties were evaluated by colony formation assay and in spheroids. Reactive oxygen species (ROS) levels, DNA damage, apoptosis and ferroptosis were analyzed using flow cytometry. Oxygen consumption rate (OCR) and mitochondrial complex activity were assessed by Seahorse Analyzer. Oxygen levels were investigated using fiber-optic sensors. The in vitro findings were validated in CT26-bearing mice. KORTUC demonstrated less cytotoxicity than H2O2-alone. KORTUC radiosensitized hypoxic tumor cells in a dose-dependent manner with enhancement ratios of 3.1 (CT26) and 2.7 (4T1). Dose-dependent OCR reduction following KORTUC exposure correlated with complex I and II inhibition, accompanied by mitochondrial ROS elevation. KORTUC injection into a 2D hypoxic tumor model surged O2 levels. KORTUC radiosensitized CT26-tumors, delaying growth by 14days. SH in KORTUC mitigates H2O2 cytotoxicity. We demonstrate that KORTUC overcomes hypoxia-induced radioresistance through inhibition of OCR, via complex I- and II-blockade, leading to tumor reoxygenation. Understanding KORTUC's pathways is essential for developing effective cancer combination therapies.
Published Version
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