Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair

Nikitaki, Zacharenia; Velalopoulou, Anastasia; Zanni, Vassiliki; Tremi, Ioanna; Havaki, Sophia; Kokkoris, M.; Gorgoulis, Vassilis G.; Koumenis, Constantinos; Georgakilas, Alexandros G.

doi:10.1017/erm.2022.6

Cited by 36 publications

(39 citation statements)

References 187 publications

(196 reference statements)

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“…Carbon ions kill cells twice or three times more effectively than protons and conventional radiation modalities [ 11 ]. In general, high-LET types induce more DSBs per dose unit, and more complex and dense lesions than low-LET types because they deposit large amounts of energy within a small distance [ 12 ]. The type of initial DNA damage largely determines the repair pathway that is subsequently activated.…”

Section: Introductionmentioning

confidence: 99%

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

et al. 2022

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Ionizing radiation (IR) is a genuine genotoxic agent and a major modality in cancer treatment. IR disrupts DNA sequences and exerts mutagenic and/or cytotoxic properties that not only alter critical cellular functions but also impact tissues proximal and distal to the irradiated site. Unveiling the molecular events governing the diverse effects of IR at the cellular and organismal levels is relevant for both radiotherapy and radiation protection. Herein, we address changes in the expression of mammalian genes induced after the exposure of a wide range of tissues to various radiation types with distinct biophysical characteristics. First, we constructed a publicly available database, termed RadBioBase, which will be updated at regular intervals. RadBioBase includes comprehensive transcriptomes of mammalian cells across healthy and diseased tissues that respond to a range of radiation types and doses. Pertinent information was derived from a hybrid analysis based on stringent literature mining and transcriptomic studies. An integrative bioinformatics methodology, including functional enrichment analysis and machine learning techniques, was employed to unveil the characteristic biological pathways related to specific radiation types and their association with various diseases. We found that the effects of high linear energy transfer (LET) radiation on cell transcriptomes significantly differ from those caused by low LET and are consistent with immunomodulation, inflammation, oxidative stress responses and cell death. The transcriptome changes also depend on the dose since low doses up to 0.5 Gy are related with cytokine cascades, while higher doses with ROS metabolism. We additionally identified distinct gene signatures for different types of radiation. Overall, our data suggest that different radiation types and doses can trigger distinct trajectories of cell-intrinsic and cell-extrinsic pathways that hold promise to be manipulated toward improving radiotherapy efficiency and reducing systemic radiotoxicities.

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Section: Introductionmentioning

confidence: 99%

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

et al. 2022

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“…protons, carbon ions, α -particle-emitting radionuclides) can differentially affect cell fate ( 317 ). For example, protons mainly induce apoptosis not necrosis which may reduce the leakage of nucleic acids into the cytoplasm to serve as danger signals, hence impacting on the innate immune response ( 317 ). The effects of radiotherapy were previously thought to be mainly due to nuclear DNA damage and their repair mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy

et al. 2022

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Radiotherapy is one of the most effective and frequently used treatments for a wide range of cancers. In addition to its direct anti-cancer cytotoxic effects, ionising radiation can augment the anti-tumour immune response by triggering pro-inflammatory signals, DNA damage-induced immunogenic cell death and innate immune activation. Anti-tumour innate immunity can result from recruitment and stimulation of dendritic cells (DCs) which leads to tumour-specific adaptive T-cell priming and immunostimulatory cell infiltration. Conversely, radiotherapy can also induce immunosuppressive and anti-inflammatory mediators that can confer radioresistance. Targeting the DNA damage response (DDR) concomitantly with radiotherapy is an attractive strategy for overcoming radioresistance, both by enhancing the radiosensitivity of tumour relative to normal tissues, and tipping the scales in favour of an immunostimulatory tumour microenvironment. This two-pronged approach exploits genomic instability to circumvent immune evasion, targeting both hallmarks of cancer. In this review, we describe targetable DDR proteins (PARP (poly[ADP-ribose] polymerase); ATM/ATR (ataxia–telangiectasia mutated and Rad3-related), DNA-PKcs (DNA-dependent protein kinase, catalytic subunit) and Wee1 (Wee1-like protein kinase) and their potential intersections with druggable immunomodulatory signalling pathways, including nucleic acid-sensing mechanisms (Toll-like receptors (TLR); cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and retinoic acid-inducible gene-I (RIG-I)-like receptors), and how these might be exploited to enhance radiation therapy. We summarise current preclinical advances, recent and ongoing clinical trials and the challenges of therapeutic combinations with existing treatments such as immune checkpoint inhibitors.

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“…The biological effects of ionizing radiation vary hugely with radiation quality, from sparsely ionizing photons and electrons to protons and densely ionizing heavier ions such as carbon or iron ions. This has been addressed in dedicated radiobiological studies investigating endpoints such as DNA damage induction, its repair, induction of chromosomal aberrations, mutations or cell killing; reviewed, for example, by [ 1 , 2 , 3 , 4 , 5 ]. Modelling and simulation tools, especially Monte Carlo track structure simulations, have succeeded in explaining the observed trends and linking them to the initial physical processes that lead to distinct track structures, as well as subsequent chemical processes of radical formation, reactions, and attack on cellular DNA [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Track Structure-Based Simulations on DNA Damage Induced by Diverse Isotopes

Kundrát

Friedland

Baiocco

2022

IJMS

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Diverse isotopes such as 2H, 3He, 10Be, 11C and 14C occur in nuclear reactions in ion beam radiotherapy, in cosmic ray shielding, or are intentionally accelerated in dating techniques. However, only a few studies have specifically addressed the biological effects of diverse isotopes and were limited to energies of several MeV/u. A database of simulations with the PARTRAC biophysical tool is presented for H, He, Li, Be, B and C isotopes at energies from 0.5 GeV/u down to stopping. The doses deposited to a cell nucleus and also the yields per unit dose of single- and double-strand breaks and their clusters induced in cellular DNA are predicted to vary among diverse isotopes of the same element at energies < 1 MeV/u, especially for isotopes of H and He. The results may affect the risk estimates for astronauts in deep space missions or the models of biological effectiveness of ion beams and indicate that radiation protection in 14C or 10Be dating techniques may be based on knowledge gathered with 12C or 9Be.

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Key biological mechanisms involved in high-LET radiation therapies with a focus on DNA damage and repair

Cited by 36 publications

References 187 publications

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy

Track Structure-Based Simulations on DNA Damage Induced by Diverse Isotopes

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