| Title: | Hyperthermia as a potential cornerstone of effective multimodality treatment with radiotherapy, cisplatin and PARP inhibitor in IDH1-mutated cancer cells |
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| Authors: | ID Khurshed, Mohammed (Author)
ID Prades-Sagarra, Elia (Author)
ID Al Saleh, Sarah (Author)
ID Sminia, Peter (Author)
ID Wilmink, Johanna W (Author)
ID Molenaar, Remco J. (Author)
ID Crezee, Hans (Author)
ID Noorden, Cornelis J. F. van (Author) |
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| Files: |  URL - Source URL, visit https://doi.org/10.3390/cancers14246228
 PDF - Presentation file, download (2,26 MB)
MD5: 7647330C54A03C1C14AD2CA5BBA142A1
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  NIB - National Institute of Biology
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| Abstract: | Mutations in the isocitrate dehydrogenase 1 (IDH1MUT) gene occur in various types of malignancies, including ~60% of chondrosarcomas, ~30% of intrahepatic cholangiocarcinomas and >80% of low-grade gliomas. IDH1MUT are causal in the development and progression of these types of cancer due to neomorphic production of the oncometabolite D-2-hydroxyglutarate (D-2HG). Intracellular accumulation of D-2HG has been implicated in suppressing homologous recombination and renders IDH1MUT cancer cells sensitive to DNA-repair-inhibiting agents, such as poly-(adenosine 5′-diphosphate–ribose) polymerase inhibitors (PARPi). Hyperthermia increases the efficacy of DNA-damaging therapies such as radiotherapy and platinum-based chemotherapy, mainly by inhibition of DNA repair. In the current study, we investigated the additional effects of hyperthermia (42 °C for 1 h) in the treatment of IDH1MUT HCT116 colon cancer cells and hyperthermia1080 chondrosarcoma cancer cells in combination with radiation, cisplatin and/or a PARPi on clonogenic cell survival, cell cycle distribution and the induction and repair of DNA double-strand breaks. We found that hyperthermia in combination with radiation or cisplatin induces an increase in double-strand breaks and cell death, up to 10-fold in IDH1MUT cancer cells compared to IDH1 wild-type cells. This vulnerability was abolished by the IDH1MUT inhibitor AGI-5198 and was further increased by the PARPi. In conclusion, our study shows that IDH1MUT cancer cells are sensitized to hyperthermia in combination with irradiation or cisplatin and a PARPi. Therefore, hyperthermia may be an efficacious sensitizer to cytotoxic therapies in tumors where the clinical application of hyperthermia is feasible, such as IDH1MUT chondrosarcoma of the extremities. |
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| Keywords: | isocitrate dehydrogenase, PARP, hyperthermia, D‐2‐hydroxyglutarate, radiotherapy, cisplatin |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Publication date: | 17.12.2022 |
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| Year of publishing: | 2022 |
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| Number of pages: | str. [1]-13 |
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| Numbering: | Vol. 14, iss. 24 |
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| PID: | 20.500.12556/DiRROS-19413  |
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| UDC: | 576 |
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| ISSN on article: | 2072-6694 |
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| DOI: | 10.3390/cancers14246228 |
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| COBISS.SI-ID: | 134747651 |
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| Note: | Nasl. z nasl. zaslona;
Opis vira z dne 20. 12. 2022;
Ostali avtorji: Elia Prades-Sagarra, Sarah Saleh, Peter Sminia, Johanna W. Wilmink, Remco J. Molenaar, Hans Crezee and Cornelis J. F. van Noorden;
Št. članka: 6228;
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| Publication date in DiRROS: | 18.07.2024 |
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| Views: | 270 |
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| Downloads: | 185 |
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