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Poster De Conférence Année : 2023

Glioblastoma and glioblastoma stem-like cancer cells radiosensitization to X-ray and carbon ions using ATM and ATR inhibitors

Résumé

Glioblastoma multiform (GBM) represents the deadliest brain cancer, being extremely chemo- and radioresistant. To overcome the resistance to radiotherapy, the use of DNA repair inhibitors was explored for photons and particle irradiation. The treatment with ATM (AZD1390, 10nM) and ATR (VE822, 100nM) DNA repair inhibitors in combination with X-ray and carbon ions was investigated in several commercial human GBM cell lines: U251, U87, U118, T98G and two stem-like cell lines: R633 (p53 mutated) and TG-1 (ATM missense mutation), isolated from neurosurgical biopsy of human GBM. The cells were treated with inhibitors before exposure to X-ray or carbon ion beam (28 and 73KeV/um2). Proliferation index, LDH release and senescence induction were evaluated 5 days post-irradiation. In addition, clonogenic survival was measured inU251 cells. The cell lines range from most radiosensitive to most radioresistant as follows: U87, TG-1, R633, T98G, U251, U118. ATMi induced a higher sensitization than ATRi in all cell lines, as measured by poliferation index after X-ray irradiation. The highest sensitization was induced in U87, U118 and U251 cells and the lowest in the stem-like cells, were ATRi had almost no effect. LDH release is not induced by inhibitors alone, but it is detected following irradiation alone and in combination with inhibitors. Stem-like cells presented more LDH release suggesting higher cellular death. Radiation alone and combination with DNA damage inhibitors induced senescence in the most radiosensitive cell lines (U118, U87) and in both stem-like cells. Clonogenic survival showed lower survival following carbon ions then X-ray, and moreover, a lower survival at higher LET beam. In conclusion, the proposed inhibitors are a promising tool for glioblastoma treatment in combination with radiotherapy. However, individual genetic and epigenetic background likely affects radiosensitivity and treatment response of tumor cell and can modulate the therapeutic outcome.
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Dates et versions

hal-04217139 , version 1 (25-09-2023)

Identifiants

  • HAL Id : hal-04217139 , version 1

Citer

Mihaela Temelie, Mihaela Tudor, Ana-Maria Serban, Gro Elise Rødland, Daniela Stroe, et al.. Glioblastoma and glioblastoma stem-like cancer cells radiosensitization to X-ray and carbon ions using ATM and ATR inhibitors. ICRR 2023, Aug 2023, Montréal (Quebec), Canada. ⟨hal-04217139⟩
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