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

Abstract

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⁻¹, demonstrating synergistic effects compared to either MNPs or ART treatment alone (IC50 for MNPs is 9.7 μg mL⁻¹ and for ART is 9.4 μg mL⁻¹ 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.