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Hyperthermia is used in combination with radiation therapy to enhance the radiation response of the target tumor. However, many tumors are thermoresistant, which makes the thermo-radiosensitization ineffective. In this work, we studied a possibility of enhancing the radiosensitiz-ing effect of hyperthermia on cancer cells in the case of combining heating and treatments with inhibitors of proteasomal protein degradation. The objects of the study were HeLa, MCF-7, and PC-3 cell lines derived from human carcinomas of various localization. Before irradiation (2-6 Gy), cell cultures were subjected to heat stress (42-44 °C for 20-60 min) without or in the pres-ence of proteasome inhibitors (MG132, bortezomib). The death and survival of the treated cells was evaluated by the level of apoptosis/necrosis, by clonogenicity, and in the MTT test. The pro-teotoxicity of the exposures and the subcellular redistribution of heat shock proteins were ana-lyzed using cell fractionation, electrophoresis, and immunoblotting. The results show that, com-pared with hyperthermia, the combined effect (hyperthermia + proteasome inhibitor) significantly increased the radiosensitization of cancer cells, which was manifested in the intensification of their postradiation death and significant suppression of clonogenicity. Thus, the combination of hyperthermia with proteasome inhibitors (for example, with bortezomib, which is clinically ap-proved) can help sensitize radioresistant tumors to radiation therapy.

Enhanced radiosensitization of tumor cells by means of the combined exposure of hyperthermia and proteasome inhibitors