Perturbation of hyperthermia resistance in gastric cancer by hyperstimulation of autophagy using artemisinin-protected iron-oxide nanoparticles.

In a bid to overcome hyperthermia resistance, a major obstacle in cancer treatment, this study explores manipulating autophagy, a cellular recycling mechanism, within the context of gastric cancer. We designed artemisinin-protected magnetic iron-oxide nanoparticles (ART-MNPs) to hyperactivate autophagy, potentially sensitizing cancer cells to hyperthermia. The synthesized ART-MNPs exhibited magnetic properties and the capability of raising the temperature by 7 °C at 580.3 kHz. Importantly, ART-MNPs displayed significant cytotoxicity against human gastric cancer cells (AGS), with an IC50 value of 1.9 μg mL, demonstrating synergistic effects compared to either MNPs or ART treatment alone (IC50 for MNPs is 9.7 μg mL and for ART is 9.4 μg mL respectively). Combination index studies further supported this synergy. Mechanistic analysis revealed a significant increase in autophagy level (13.58- and 15.08-fold increase compared to artemisinin and MNPs, respectively) upon ART-MNP treatment, suggesting that this hyperactivation is responsible for hyperthermia sensitization and minimized resistance (as evidenced by changes in viability compared to control under hyperthermic conditions). This work offers a promising strategy to modulate autophagy and overcome hyperthermia resistance, paving the way for developing hyperthermia as a standalone therapy for gastric cancer.