Targeting DNA double strand break repair with hyperthermia and DNA-PKcs inhibition to enhance the effect of radiation treatment
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Bregje van Oorschot1, Giovanna Granata1, Simone Di Franco2, Rosemarie ten Cate1, Hans M. Rodermond1, Matilde Todaro3, Jan Paul Medema1, Nicolaas A.P. Franken1
1Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine, Department of Radiation Oncology, Academic Medical Center, Cancer Genomics Center, Amsterdam, The Netherlands
2Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy
3Biomedical Department of Internal and Specialistic Medicine (DIBIMIS), University of Palermo, Palermo, Italy
Nicolaas A.P. Franken, email: firstname.lastname@example.org
Keywords: radiation oncology, DNA repair, hyperthermia, double-strand breaks
Received: May 10, 2016 Accepted: August 24, 2016 Published: September 01, 2016
Radiotherapy is based on the induction of lethal DNA damage, primarily DNA double-strand breaks (DSB). Efficient DSB repair via Non-Homologous End Joining or Homologous Recombination can therefore undermine the efficacy of radiotherapy. By suppressing DNA-DSB repair with hyperthermia (HT) and DNA-PKcs inhibitor NU7441 (DNA-PKcsi), we aim to enhance the effect of radiation.
The sensitizing effect of HT for 1 hour at 42°C and DNA-PKcsi [1 μM] to radiation treatment was investigated in cervical and breast cancer cells, primary breast cancer sphere cells (BCSCs) enriched for cancer stem cells, and in an in vivo human tumor model. A significant radio-enhancement effect was observed for all cell types when DNA-PKcsi and HT were applied separately, and when both were combined, HT and DNA-PKcsi enhanced radio-sensitivity to an even greater extent. Strikingly, combined treatment resulted in significantly lower survival rates, 2 to 2.5 fold increase in apoptosis, more residual DNA-DSB 6 h post treatment and a G2-phase arrest. In addition, tumor growth analysis in vivo showed significant reduction in tumor growth and elevated caspase-3 activity when radiation was combined with HT and DNA-PKcsi compared to radiation alone. Importantly, no toxic side effects of HT or DNA-PKcsi were found.
In conclusion, inhibiting DNA-DSB repair using HT and DNA-PKcsi before radiotherapy leads to enhanced cytotoxicity in cancer cells. This effect was even noticed in the more radio-resistant BCSCs, which are clearly sensitized by combined treatment. Therefore, the addition of HT and DNA-PKcsi to conventional radiotherapy is promising and might contribute to more efficient tumor control and patient outcome.
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