AGuIX nanoparticles enhance ionizing radiation-induced ferroptosis on tumor cells by targeting the NRF2-GPX4 signaling pathway

Abstract

In the frame of radiotherapy treatment of cancer, radioresistance remains a major issue that still needs solutions to be overcome. To effectively improve the radiosensitivity of tumors and reduce the damage of radiation to neighboring normal tissues, radiosensitizers have been given increasing attention in recent years. As nanoparticles based on the metal element gadolinium, AGuIX nanoparticles have been shown to increase the radiosensitivity of cancers. Although it is a rare nanomaterial that has entered preclinical trials, the unclear biological mechanism hinders its further clinical application. In this study, we demonstrated the effectiveness of AGuIX nanoparticles in the radiosensitization of triple-negative breast cancer. We found that AGuIX nanoparticles increased the level of DNA damage by compromising the homologous recombination repair pathway instead of the non-homologous end joining pathway. Moreover, the results showed that AGuIX nanoparticles induced apoptosis, but the degree of apoptosis ability was very low, which cannot fully explain their strong radiosensitizing effect. Ferroptosis, the other mode of cell death, was also discovered to play a significant role in radiation sensitization, and AGuIX nanoparticles may regulate the anti-ferroptosis system by inhibiting the NRF2-GSH-GPX4 signaling pathway.

Synergistic Effect of Ferroptosis‐Inducing Nanoparticles and X‐Ray Irradiation Combination Therapy

“…A few studies have proposed ferroptosis-inducing nanoparticles in combination with ionizing radiation, nevertheless, they are still far from actual clinical application. [33][34][35][36] Monte Carlo simulations are a valuable tool to simulate the behavior of complex systems, such as the interaction between ionizing radiation and materials that are commonly used in cancer therapy. [37][38][39][40] We can accurately predict the radial dose distributions around nanoparticles, which may provide valuable insights into the physical means of the combination of nanoparticles with ionizing radiation.…”