Overexpression of
heat shock protein 90 (HSP90) is associated with increased
tumor cell survival and radioresistance. In this study we explored the efficacy of the novel HSP90 inhibitor
AT13387 and examined its
radiosensitizing effects in combination with gamma-radiation in 2D and 3D structures as well as mice-xenografts.
AT13387 induced effective cytotoxic activity and radiosensitized
cancer cells in monolayer and
tumor spheroid models, where low
drug doses triggered significant synergistic effects on cell survival together with radiation. Furthermore,
AT13387 treatment resulted in G2/M-phase arrest and significantly reduced the migration capacity. The expression of selected client
proteins involved in DNA repair, cell-signaling and cell growth was downregulated in vitro, though the expression of most investigated
proteins recurred after 8-24 h. These results were confirmed in vivo where
AT13387 treated
tumors displayed effective downregulation of HSP90 and its oncogenic client
proteins.In conclusion, our results demonstrate that
AT13387 is a potent new
cancer drug and effective radiosensitizer in vitro with an excellent in vivo efficacy.
AT13387 treatment has the potential to improve external beam
therapy and
radionuclide therapy outcomes and restore treatment efficacy in
cancers that are resistant to initial therapeutic regimes.