Hyperthermia as a Method to Increase the Radiosensitivity of Tumor Cells Unsusceptible to Pharmacological Radiosensitizers

摘要

The possibility of using hyperthermia for the efficient radiosensitization of tumor cells with radioand chemoresistant phenotype was tested in an in vitro model. The work was carried out on MCF-7/MDR1 line cells derived from a human breast carcinoma and demonstrating the phenomenon of multidrug resistance due to overexpression of the MDR1 gene. The tumor cells of the maternal MCF-7 line were used in the comparative experiments. The cell cultures were exposed to heat stress (42-44 degrees C, 30-90 min), then to the action of gamma-radiation in doses of 2-8 Gy. Cytotoxic effects were estimated in the MTT test, as well as by the intensity of apoptosis and necrosis or a decrease in clonogenicity. The transcriptional stress response of heated cells was studied using real-time PCR, determining the accumulation of mRNA encoding inducible heat shock proteins HSP70 and HSP27. It was established that MCF-7/MDR1 radio- and chemoresistant cells do not have increased thermoresistance, and their responses to heat stress are comparable to those for MCF-7 cells. At the same time, it was demonstrated that hyperthermal pretreatment allows a significant enhancement of the cytotoxic effect of gamma-radiation on MCF-7/MDR1 cells, which proves the possibility of the efficient use of hyperthermia to increase the sensitivity to radiation of radioresistant tumors that have multidrug resistance and are unsusceptible to chemotherapeutic radiosensitizers. The molecular mechanisms of thermo-radiosensitization of tumor cells are considered.