Revisiting hydrogen peroxide as radiosensitizer for solid tumor cells.
F Geirnaert1, L Kerkhove1, A Rifi1
1Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
Summary
Kochi Oxydol-Radiation for Unresectable Carcinomas (KORTUC), a combination of hydrogen peroxide and sodium hyaluronate, effectively overcomes tumor hypoxia-induced radioresistance. This novel therapy inhibits oxygen consumption, leading to tumor reoxygenation and enhanced radiosensitivity.
Area of Science:
- Oncology
- Radiation Oncology
- Cancer Biology
Background:
- Tumor hypoxia is a primary driver of radioresistance in cancer treatment.
- Hydrogen peroxide (H2O2) acts as a radiosensitizer but faces clinical challenges due to stability and toxicity.
- Sodium hyaluronate (SH) is utilized to improve H2O2 delivery and stability for intratumoral administration.
Purpose of the Study:
- To investigate the radiomodulatory effects and underlying mechanisms of Kochi Oxydol-Radiation for Unresectable Carcinomas (KORTUC) in hypoxic tumor models.
- To evaluate the efficacy of KORTUC in overcoming hypoxia-induced radioresistance.
- To assess the safety and therapeutic potential of KORTUC as a combination therapy.
Main Methods:
- In vitro studies exposed CT26 and 4T1 cells to H2O2, SH, and KORTUC under hypoxic conditions.
- Toxicity was assessed via MTT assays and live-cell analysis; radiosensitizing properties were evaluated using colony formation assays and spheroid models.
- Mechanisms investigated included reactive oxygen species (ROS) levels, DNA damage, apoptosis, ferroptosis, oxygen consumption rate (OCR), mitochondrial complex activity, and intratumoral oxygen levels.
- In vivo validation was performed in CT26-bearing mice.
Main Results:
- KORTUC exhibited reduced cytotoxicity compared to H2O2 alone.
- KORTUC demonstrated dose-dependent radiosensitization of hypoxic tumor cells, with enhancement ratios of 3.1 for CT26 and 2.7 for 4T1.
- KORTUC treatment led to decreased OCR, inhibition of mitochondrial complexes I and II, and elevated mitochondrial ROS.
- Intratumoral injection of KORTUC increased oxygen levels in a 2D hypoxic model and delayed CT26 tumor growth by 14 days in mice.
Conclusions:
- Sodium hyaluronate (SH) in KORTUC effectively mitigates the cytotoxicity of hydrogen peroxide (H2O2).
- KORTUC overcomes hypoxia-induced radioresistance by inhibiting oxygen consumption via mitochondrial complex I and II blockade, promoting tumor reoxygenation.
- Understanding these mechanisms is crucial for developing advanced cancer combination therapies involving KORTUC.
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