DNA damage response of clinical carbon ion versus photon radiation in human glioblastoma cells. (April 2019)

• Record Type: Journal Article
• Authors: Lopez Perez, Ramon; Nicolay, Nils H.; Wolf, Jörg-Christian; Frister, Moritz; Schmezer, Peter; Weber, Klaus-Josef; Huber, Peter E.
• Is Part Of: Radiotherapy and oncology. Volume 133(2019)
• Page Start: 77
• Page End: 86
• Publication Date: 2019-04
• Subjects: ATM ataxia telangiectasia mutated -- BRCA1 Breast cancer type 1 susceptibility protein -- CDK1 cyclin-dependent kinase 1 -- Chk2 checkpoint kinase 2 -- DAPI 4′, 6-Diamidin-2-phenylindol -- DMEM Dulbecco's Modified Eagle's Medium -- DSB DNA double-strand break -- FCS fetal calf serum -- GAPDH glyceraldehyde 3-phosphate dehydrogenase -- HPRT1 hypoxanthine-guanine phosphoribosyltransferase -- HR homologous recombination -- LET linear energy transfer -- NHEJ non-homologous end-joining -- PARP poly(ADP-ribose) polymerase -- PCR polymerase chain reaction -- PTEN phosphatase and tensin homolog -- RBE relative biological effectiveness -- RI relative γH2AX induction -- SOBP spread-out Bragg peak -- XRCC3 X-ray repair cross-complementing protein 3; Carbon ion radiotherapy -- Glioblastoma -- DNA double-strand breaks -- DNA repair -- Homologous recombination; Oncology -- Periodicals; Radiotherapy -- Periodicals; Tumors -- Periodicals; Medical Oncology -- Periodicals; Neoplasms -- radiotherapy -- Periodicals; Radiotherapy -- Periodicals; Radiothérapie -- Périodiques; Cancérologie -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9940642
• DOI: 10.1016/j.radonc.2018.12.028
• Languages: English
• ISSNs: 0167-8140

Abstract

Highlights: Carbon ions induced more severe DNA double-strand breaks than photons. Carbon ion-induced double-strand breaks were repaired slower and less efficiently. Carbon ions led to stronger cell cycle arrest and more apoptosis than photons. PTEN−/− cells were more dependent on homologous recombination after carbon ions versus photons. Abstract: Background and purpose: Carbon ion radiotherapy is a promising therapeutic option for glioblastoma patients due to its high physical dose conformity and greater biological effectiveness than photons. However, the biological effects of carbon ion radiation are still incompletely understood. Here, we systematically compared the biological effects of clinically used carbon ion radiation to photon radiation with emphasis on DNA repair. Materials and methods: Two human glioblastoma cell lines (U87 and LN229) were irradiated with carbon ions or photons and DNA damage response was systematically analyzed, including clonogenic survival, induction and repair of DNA double-strand breaks (DSBs), cell cycle arrest and apoptosis or autophagy. γH2AX foci were analyzed by flow cytometry, conventional light microscopy and 3D superresolution microscopy. Results: DSBs were repaired delayed and with slower kinetics after carbon ions versus photons. Carbon ions caused stronger and longer-lasting cell cycle delays, predominantly in G2 phase, and a higher rate of apoptosis. Compared to photons, the effectiveness of carbon ions was less cell cycle-dependent. Homologous recombination (HR) appeared to be more important for DSB repair after carbon ions versus photons in phosphatase and tensin homolog (PTEN)-deficient U87 cells, as opposed to PTEN-proficient LN229 cells. Conclusion: Carbon ions induced more severe DSB damage than photons, which was repaired less efficiently in both cell lines. Thus, carbon ion radiotherapy may help to overcome resistance mechanisms of glioblastoma associated with DNA repair for example in combination with repair pathway-specific drugs in the context of personalized radiotherapy.