Radiation biology. Radioecology
ISSN: 0869-8031

Archives → 2018 → Vol. 58, No. 1 → pp. 26-34

Article

Enhanced Radiosensitization of Tumor Cells by Means of Combination of Inhibitors of Chaperone Activity and Chaperone Expression

Kudryavtsev V.A.¹, Khokhlova A.V.¹, Selivanova E.I.¹, Mosina V.A.¹, Makarova Yu. M.¹, Kabakov A.E.¹

¹ A.F. Tsyb Medical Radiological Research Center, Ministry of Health of the Russian Federation, Obninsk, Russia

Abstract

Inhibitors of the heat shock protein 90 (HSP90) chaperone activity have been characterized as radiosensitizers of tumor cells, and the prospects for their application in radiotherapy are currently discussed. However, the HSP90 chaperone dysfunction in target cells leads to activation of the transcriptional factor HSF1 and then to the HSF1-mediated expression of other inducible chaperones, HSP70 and HSP27, which possess radioprotective properties and obviously impair the radiosensitizing effects of the HSP90 inhibitors used. To avoid this and strengthen the radiosenstizing impact on target tumors we propose to combine inhibitors of the HSP90 chaperone activity with inhibitors of the HSF1-dependent HSP induction. It follows from our data: if in tumor cells (HeLa, MCF-7, KTC-1) treated with the HSP90 activity inhibitors (17AAG, geldanamycin, radicicol), the HSP induction is blocked by known inhibitors of HSF1 (quercetin, KNK437, triptolide, NZ28), this yields much stronger radiosensitization than in the case of treatment with the HSP90 activity inhibitors alone. Importantly, no radiosensitization was observed in non-tumor cells (293, BJ) subjected to the same combined inhibitory treatment. It is also discussed that the suggested combination of the inhibitor of the HSP90 activity + inhibitor of the HSP induction will selectively enhance the radiation response of target tumors without aggravation of radiation damage to the surrounding normal tissues.