Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency
Background and purpose: Radiotherapy induces tumor cell killing by generating DNA double strand breaks (DSBs). The effectiveness of radiotherapy is significantly influenced by the repair of DSBs, which counteracts this lethal effect. Current investigations are focused on determining whether non-homo...
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Elsevier
2025-03-01
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| Series: | Clinical and Translational Radiation Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405630824001757 |
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| author | Tim Heemskerk Gerarda van de Kamp Marta Rovituso Roland Kanaar Jeroen Essers |
| author_facet | Tim Heemskerk Gerarda van de Kamp Marta Rovituso Roland Kanaar Jeroen Essers |
| author_sort | Tim Heemskerk |
| collection | DOAJ |
| description | Background and purpose: Radiotherapy induces tumor cell killing by generating DNA double strand breaks (DSBs). The effectiveness of radiotherapy is significantly influenced by the repair of DSBs, which counteracts this lethal effect. Current investigations are focused on determining whether non-homologous end joining (NHEJ) or homologous recombination is the predominant repair pathway following proton and photon radiation. Materials and methods: In this study, we examined the response of FaDu cells, a head and neck squamous cell carcinoma model, to spread-out Bragg peak (SOBP) proton and photon radiation combined with mild hyperthermia (42 °C for one hour) to induce homologous recombination deficiency or NHEJ inhibition by AZD7648. Results: Hyperthermia resulted in stronger radiosensitization after proton radiation (SR = 1.53) compared to photon radiation (SR = 1.32). Conversely, NHEJ inhibition did not produce a significant differential effect between photon and proton radiation. This indicates a greater reliance on homologous recombination following proton radiation compared to photon radiation. We found that the number of DSBs formed after photon versus proton irradiation is comparable. Interestingly, the homologous recombination protein Rad51 accumulated more frequently at DSBs following proton irradiation than photon irradiation. Conclusions: These findings support the hypothesis that cells rely more on homologous recombination to repair proton-induced DNA damage compared to photon-induced DNA damage. As clinically applied hyperthermia enhances the therapeutic effect of photon irradiation by, among other factors, inducing homologous recombination deficiency, our results suggests that hyperthermia could be more effective in combination with proton irradiation than photon irradiation. |
| format | Article |
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| institution | Kabale University |
| issn | 2405-6308 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Clinical and Translational Radiation Oncology |
| spelling | doaj-art-affad0b635a541529d749c58cfafe3222025-01-30T05:14:26ZengElsevierClinical and Translational Radiation Oncology2405-63082025-03-0151100898Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiencyTim Heemskerk0Gerarda van de Kamp1Marta Rovituso2Roland Kanaar3Jeroen Essers4Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands (the)Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands (the)R&D Department, HollandPTC, Delft, Netherlands (the)Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands (the)Department of Molecular Genetics, Oncode Institute, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands (the); Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, Netherlands (the); Department of Radiotherapy, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, Netherlands (the); Corresponding author.Background and purpose: Radiotherapy induces tumor cell killing by generating DNA double strand breaks (DSBs). The effectiveness of radiotherapy is significantly influenced by the repair of DSBs, which counteracts this lethal effect. Current investigations are focused on determining whether non-homologous end joining (NHEJ) or homologous recombination is the predominant repair pathway following proton and photon radiation. Materials and methods: In this study, we examined the response of FaDu cells, a head and neck squamous cell carcinoma model, to spread-out Bragg peak (SOBP) proton and photon radiation combined with mild hyperthermia (42 °C for one hour) to induce homologous recombination deficiency or NHEJ inhibition by AZD7648. Results: Hyperthermia resulted in stronger radiosensitization after proton radiation (SR = 1.53) compared to photon radiation (SR = 1.32). Conversely, NHEJ inhibition did not produce a significant differential effect between photon and proton radiation. This indicates a greater reliance on homologous recombination following proton radiation compared to photon radiation. We found that the number of DSBs formed after photon versus proton irradiation is comparable. Interestingly, the homologous recombination protein Rad51 accumulated more frequently at DSBs following proton irradiation than photon irradiation. Conclusions: These findings support the hypothesis that cells rely more on homologous recombination to repair proton-induced DNA damage compared to photon-induced DNA damage. As clinically applied hyperthermia enhances the therapeutic effect of photon irradiation by, among other factors, inducing homologous recombination deficiency, our results suggests that hyperthermia could be more effective in combination with proton irradiation than photon irradiation.http://www.sciencedirect.com/science/article/pii/S2405630824001757DNA breaksDouble-strandedProton therapyRad51 recombinaseSquamous cell carcinoma of head and neckHyperthermia |
| spellingShingle | Tim Heemskerk Gerarda van de Kamp Marta Rovituso Roland Kanaar Jeroen Essers Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency Clinical and Translational Radiation Oncology DNA breaks Double-stranded Proton therapy Rad51 recombinase Squamous cell carcinoma of head and neck Hyperthermia |
| title | Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency |
| title_full | Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency |
| title_fullStr | Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency |
| title_full_unstemmed | Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency |
| title_short | Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency |
| title_sort | enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia induced homologous recombination deficiency |
| topic | DNA breaks Double-stranded Proton therapy Rad51 recombinase Squamous cell carcinoma of head and neck Hyperthermia |
| url | http://www.sciencedirect.com/science/article/pii/S2405630824001757 |
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