Thermosensitization of tumor cells with inhibitors of chaperone activity and expression

   
Kudryavtsev V.A.1, Makarova Y.M.1, Kabakov A.E.1

1. Medical Radiology Research Center, Russian Academy of Medical Sciences
Section: Experimental/Clinical Study
DOI: 10.18097/pbmc20125806662      UDK: 577.112.2:615.832.8:616-006.4      PubMed Id: 23350198
Year: 2012  Volume: 58  Issue: 6  Pages: 662-672
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 chaperone-dependent reactivation of a thermo-labile reporter (luciferase) in heat-stressed HeLa cells and slightly enhanced their death following incubation for 60 min at 43°C. Herein, the inhibitors of HSP90 activity stimulated de novo induction of additional chaperones (HSP70 and HSP27) that significantly increased the intracellular HSP levels. If the cells were treated with 17AAG or radicicol along with an inhibitor of the HSP induction (e.g. quercetin or triptolid, or NZ28), this fully prevented the increase in intracellular chaperone levels resulting from the inhibition of HSP90 activity and subsequent heating. Importantly, in the case of conjunction of all the three treatments (an inhibitor of the HSP90 activity + an inhibitor of the HSP induction + 43°C for 60 min), the reporter reactivation was retarded yet stronger while the cell death was sharply (2-3-fold) enhanced. Such an enhancement of the cytotoxicity appears to occur owing 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.
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Kudryavtsev V.A., Makarova Y.M., Kabakov A.E. (2012) Biomeditsinskaya khimiya, 58(6), 662-672.
This paper is also available as the English translation:10.1134/S1990750812010088
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