Inhibition of the heat shock protein 90 activity: approaches to the selective radiosensitization of tumors

Heat shock protein 90 (HSP90) is involved in regulatory and signal responses ensuring the radioresistance of cancer cells. Possibilities are considered towards inhibition of this protein for radiosensitizing malignant tumors and increasing the efficacy of radiation therapy. In the present study, effects were compared of known inhibitors of the functional activity of HSP90 (geldanamycin, radicicol, 17AAG) on the radiosensitivity of cell lines derived from human carcinomas (Hela, MCF-7, KTC-1) and normal tissues (293, BJ). After the inhibitory pretreatment of cells and subsequent γ -radiation exposure at 2-8 Gy, such parameters were evaluated as the cell viability and clonogenicity, and also amounts of double-strand DNA breaks and dynamics of their repair. It follows from the data obtained that, using nanomolar (i.e. clinically achievable) concentrations of the HSP90 activity inhibitors, it was possible to induce significant radiosensitization of tumor cells without any increasing the radisensitivity of normal cells. At the molecular level, the selective radiosensitizing action of inhibitors of the HSP90 activity was due to a retardation of repair processes in nuclear DNA of irradiated cancer cells and the absence of analogous effect in irradiated normal cells. Such results allow to hope that HSP90 activity inhibitor-based radiosensitizers will selectively enhance the radiation response of tumors with no increasing a risk of complications through radiation damage to adjacent normal tissues.