Identification of thermal sensitizers that enhance heat stress-induced apoptosis

Abstract Hyperthermia has emerged as a therapeutic approach for cancer treatment by inducing apoptotic cell death through exposure to elevated temperatures. Nevertheless, the antitumor efficacy of hyperthermia is frequently compromised by variations in tumor characteristics and adaptive cellular responses that promote thermotolerance. To improve therapeutic outcomes, hyperthermia has been combined with thermal sensitizers, such as chemotherapeutic drugs, capable of increasing cellular sensitivity to heat stress. In our previous study, SB366791, an inhibitor of heat stress-induced scaffold attachment factor B granule formation, promoted apoptosis under heat stress conditions; however, its ability to induce apoptosis was limited. Therefore, we conducted a chemical library screening to identify more potent thermal sensitizers that could augment heat stress-mediated apoptosis. Six candidate compounds were identified as enhancers of heat-induced apoptosis in HeLa cells. Notably, these compounds exhibited greater pro-apoptotic effects under heat stress conditions than 5-fluorouracil. In addition, under normal conditions, Z134808806, Z228922334, Z198049864, and Z318719814 caused cell cycle arrest at the G1 phase, whereas Z134809032 induced G2/M phase arrest. Collectively, these findings suggest that the identified compounds may serve as effective thermal sensitizers and provide potential candidates for improving hyperthermia-based anticancer strategies.