Abstract
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.
Highlights
Cancer treatments have undergone dramatic improvement during the last century, much due to our increasing molecular understanding of this elusive disease category
At a radiation dose of 4 Gy, 22% of H314 were able to grow into a colony, while combination treatment with 0.5 nM AT13387 reduced the survival by a factor of 2, to 11%
When comparing survival fractions from combination treatment with calculated expected survival fractions Sexp from single treatments, statistically significant radiosensitizing and synergistic effects could be seen on all cell lines for 50 nM AT13387 and radiation doses of 2, 4 and 6 Gy (p < 0.05)
Summary
Cancer treatments have undergone dramatic improvement during the last century, much due to our increasing molecular understanding of this elusive disease category. An increased expression level of HSP90 has been found in several hematologic and solid tumors, including squamous cell carcinomas of the head www.impactjournals.com/oncotarget and neck region (HNSCC) [9] and adenocarcinomas [10,11,12,13]. This overexpression is associated with increased tumor cell survival, an effect that is probably due to stabilization of oncogenic cell signaling proteins, which prohibits apoptosis. Stabilization of constitutively activated signaling proteins, like AKT and ERK, promotes uncontrollable growth
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