Thermosensitization of tumor cells with inhibitors of chaperone activity and expression

• Published in: Biochemistry (Moscow). Supplement. Series B, Biomedical chemistry Vol. 6; no. 1; pp. 61 - 67
• Main Authors: Kudryavtsev, V. A., Makarova, Yu. M., Kabakov, A. E.
• Format: Journal Article
• Language: English
• Published: Dordrecht SP MAIK Nauka/Interperiodica 01.03.2012; Springer Nature B.V
• Subjects: Bioorganic Chemistry; Cells; Chemistry; Chemistry and Materials Science; Gene expression; Medicinal Chemistry; Tumors; hyperthermia; thermoresistance; heat shock proteins; HSF1
• ISSN: 1990-7508; 1990-7516
• DOI: 10.1134/S1990750812010088

Effects of inhibitors of the heat shock protein 90 (HSP90) chaperone activity and inhibitors of the heat shock protein (HSP) expression on sensitivity of HeLa tumor cells to hyperthermia were studied. It was found that nanomolar concentrations of inhibitors of the HSP90 activity (17AAG or radicicol) slowed down the chaperone-dependent reactivation of a thermolabile reporter (luciferase) in heat-stressed HeLa cells and slightly enhanced their death following the incubation for 60 min at 43°C. The inhibitors of HSP90 activity stimulated de novo induction of additional chaperones (HSP70 and HSP27) that significantly increased intracellular HSP levels. Treatment of the cells with 17AAG or radicicol along with an inhibitor of the HSP induction (e.g. quercetin or triptolide, or NZ28) completely prevented the increase in the intracellular chaperone levels resulting from the inhibition of HSP90 activity and subsequent heating. Combination of all three treatments (inhibition of the HSP90 activity + inhibition of the HSP induction + heating at 43°C for 60 min) resulted in more potent inhibition of the reporter reactivation and a sharp (2–3-fold) increase in cell death. Such enhancement of the cytotoxicity may be attributed to the “chaperone deficiency” when prior to heat stress both the functional activity of constitutive HSP90 and the expression of additional (inducible) chaperones are blocked in the cells.