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Radiation as a Double-Edged Sword: Cancer Therapy and Potential Harm

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (15 April 2024) | Viewed by 8617

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Prof. Dr. Francis Cucinotta

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Guest Editor

Department of Health Physics and Diagnostic Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
Interests: radiation health effects; space radiation; radiation cancer risk; radiation neurological effects; biophysics models; high LET radiobiology

Special Issue Information

Dear Colleagues,

Radiation continues to be viewed as a double-edged sword with respect to its benefits in cancer treatment and potential harm in normal tissue effects. In addition, to the risks of late effects such as cancer and circulatory as well as neurological diseases. Of note is the significant overlap in approaches to elucidate radiobiological mechanisms in the areas of radiation cancer treatment as well as the risks in the diagnostic use of radiation and to radiation workers on Earth and in space. In addition, there is expanding interest in advanced radiation modalities, including high-linear energy transfer (LET) and ultra-high dose rate (FLASH) irradiations. Research in these areas has made great progress in recent years, and this Special Issue aims to provide a comprehensive overview of the latest advances in the use of radiation in cancer treatment and risk assessments.

We encourage the submission of original full research papers as well as review articles dealing with novel mechanistic insights, new techniques, experimental models, predictive theoretical models, and datasets.

Topics include, but are not limited to, the following:

DNA damage responses;
Tissue-specific immune responses following radiation exposure;
Combined treatments, including immunoradiation therapy;
Cognitive impairments following radiation exposure;
Radiation circulatory disease risks;
Mechanisms of tumor control and normal tissue effects in the application of advanced radiation modalities, including FLASH irradiation, carbon ion, and other forms of high-LET radiation;
Non-targeted effects in risk assessments;
Systems biology models applied to these topics.

Prof. Dr. Francis Cucinotta
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

radiobiological mechanisms
cancer treatment
cancer risk
normal tissue effects
cognitive impairment
immune responses
DNA damage responses
systems biology
non-targeted effects
high-LET radiation
space radiation
FLASH irradiation

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Published Papers (5 papers)

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Research

15 pages, 1976 KiB

Open AccessArticle

Changes in Telomere Length in Leukocytes and Leukemic Cells after Ultrashort Electron Beam Radiation

by Tigran Harutyunyan, Anzhela Sargsyan, Lily Kalashyan, Hovhannes Igityan, Bagrat Grigoryan, Hakob Davtyan, Rouben Aroutiounian, Thomas Liehr and Galina Hovhannisyan

Int. J. Mol. Sci. 2024, 25(12), 6709; https://doi.org/10.3390/ijms25126709 - 18 Jun 2024

Viewed by 1335

Abstract

Application of laser-generated electron beams in radiotherapy is a recent development. Accordingly, mechanisms of biological response to radiation damage need to be investigated. In this study, telomere length (TL) as endpoint of genetic damage was analyzed in human blood cells (leukocytes) and K562 leukemic cells irradiated with laser-generated ultrashort electron beam. Metaphases and interphases were analyzed in quantitative fluorescence in situ hybridization (Q-FISH) to assess TL. TLs were shortened compared to non-irradiated controls in both settings (metaphase and interphase) after irradiation with 0.5, 1.5, and 3.0 Gy in blood leukocytes. Radiation also caused a significant TL shortening detectable in the interphase of K562 cells. Overall, a negative correlation between TL and radiation doses was observed in normal and leukemic cells in a dose-dependent manner. K562 cells were more sensitive than normal blood cells to increasing doses of ultrashort electron beam radiation. As telomere shortening leads to genome instability and cell death, the results obtained confirm the suitability of this biomarker for assessing genotoxic effects of accelerated electrons for their further use in radiation therapy. Observed differences in TL shortening between normal and K562 cells provide an opportunity for further development of optimal radiation parameters to reduce side effects in normal cells during radiotherapy. Full article

(This article belongs to the Special Issue Radiation as a Double-Edged Sword: Cancer Therapy and Potential Harm)

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20 pages, 13106 KiB

Open AccessArticle

Unraveling the Role of RNase L Knockout in Alleviating Immune Response Activation in Mice Bone Marrow after Irradiation

by Kexin Ding, Hujie Li, Fumin Tai, Junzhao Duan, Qiong Wang, Rui Zhai, Hanjiang Fu, Changhui Ge and Xiaofei Zheng

Int. J. Mol. Sci. 2024, 25(5), 2722; https://doi.org/10.3390/ijms25052722 - 27 Feb 2024

Viewed by 1456

Abstract

Ionizing radiation (IR) induces severe hematopoietic injury by causing DNA and RNA damage as well as activating the immune responses, necessitating the development of effective therapeutic strategies. Ribonuclease L (RNase L) as an innate immune response pathway is triggered by exogenous and endogenous abnormal dsRNA under viral infection and dyshomeostasis, thereby activating the immune responses. Thus, we investigated the effect of RNase L on irradiation-induced bone marrow damage using RNase L knockout (RNase L^−/−) mice. Phenotypic analysis revealed that RNase L knockout mitigates irradiation-induced injury in the bone marrow. Further investigation into the mechanism of RNase L by RNA-seq, qRT-PCR, and CBA analysis demonstrated that RNase L deficiency counteracts the upregulation of genes related to immune responses induced by irradiation, including cytokines and interferon-stimulated genes. Moreover, RNase L deficiency inhibits the increased levels of immunoglobulins in serum induced by irradiation. These findings indicate that RNase L plays a role in the immune response induced by irradiation in the bone marrow. This study further enhances our understanding of the biological functions of RNase L in the immune response induced by irradiation and offers a novel approach for managing irradiation-induced bone marrow injury through the regulation of RNase L activation. Full article

(This article belongs to the Special Issue Radiation as a Double-Edged Sword: Cancer Therapy and Potential Harm)

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10 pages, 1371 KiB

Open AccessArticle

Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models

by Kayla E. A. Duval, Armin D. Tavakkoli, Alireza Kheirollah, Haille E. Soderholm, Eugene Demidenko, Janet L. Lines, Walburga Croteau, Samuel C. Zhang, Robert J. Wagner, Ethan Aulwes, Randolph J. Noelle and P. Jack Hoopes

Int. J. Mol. Sci. 2023, 24(18), 13742; https://doi.org/10.3390/ijms241813742 - 6 Sep 2023

Cited by 1 | Viewed by 1476

Abstract

Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. The aim of this study is to evaluate whether and to what extent blockade of VISTA, an immune checkpoint, can potentiate the tumor control ability of radiation therapy. Our study is novel in that it is the first comparison of two VISTA-blocking methods (antibody inhibition and genetic knockout) in combination with RT. VISTA was blocked either through genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine flank tumor models (B16 and MC38). Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. When combined with a single 15Gy radiation dose, VISTA blockade via genetic knockout in the B16 model and via anti-VISTA antibodies in the MC38 model significantly improved survival compared to RT alone by an average of 5.5 days and 6.3 days, respectively (p < 0.05). The gene expression data suggest that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune-mediated cytotoxicity. VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15Gy radiation through increased expression and stimulation of cell-mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner. Full article

(This article belongs to the Special Issue Radiation as a Double-Edged Sword: Cancer Therapy and Potential Harm)

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15 pages, 1914 KiB

Open AccessArticle

Effects of UHDR and Conventional Irradiation on Behavioral and Cognitive Performance and the Percentage of Ly6G+ CD45+ Cells in the Hippocampus

by Ariel Chaklai, Pamela Canaday, Abigail O’Niel, Francis A. Cucinotta, Austin Sloop, David Gladstone, Brian Pogue, Rongxiao Zhang, Jacob Sunnerberg, Alireza Kheirollah, Charles R. Thomas, Jr., P. Jack Hoopes and Jacob Raber

Int. J. Mol. Sci. 2023, 24(15), 12497; https://doi.org/10.3390/ijms241512497 - 6 Aug 2023

Cited by 3 | Viewed by 1685

Abstract

We assessed the effects of conventional and ultra-high dose rate (UHDR) electron irradiation on behavioral and cognitive performance one month following exposure and assessed whether these effects were associated with alterations in the number of immune cells in the hippocampus using flow cytometry. Two-month-old female and male C57BL/6J mice received whole-brain conventional or UHDR irradiation. UHDR mice were irradiated with 9 MeV electrons, delivered by the Linac-based/modified beam control. The mice were irradiated or sham-irradiated at Dartmouth, the following week shipped to OHSU, and behaviorally and cognitively tested between 27 and 41 days after exposure. Conventional- and UHDR-irradiated mice showed impaired novel object recognition. During fear learning, conventional- and UHDR-irradiated mice moved less during the inter-stimulus interval (ISI) and UHDR-irradiated mice also moved less during the baseline period (prior to the first tone). In irradiated mice, reduced activity levels were also seen in the home cage: conventional- and UHDR-irradiated mice moved less during the light period and UHDR-irradiated mice moved less during the dark period. Following behavioral and cognitive testing, infiltrating immune cells in the hippocampus were analyzed by flow cytometry. The percentage of Ly6G+ CD45+ cells in the hippocampus was lower in conventional- and UHDR-irradiated than sham-irradiated mice, suggesting that neutrophils might be particularly sensitive to radiation. The percentage of Ly6G+ CD45+ cells in the hippocampus was positively correlated with the time spent exploring the novel object in the object recognition test. Under the experimental conditions used, cognitive injury was comparable in conventional and UHDR mice. However, the percentage of CD45+ CD11b+ Ly6+ and CD45+ CD11b+ Ly6G- cells in the hippocampus cells in the hippocampus was altered in conventional- but not UHDR-irradiated mice and the reduced percentage of Ly6G+ CD45+ cells in the hippocampus might mediate some of the detrimental radiation-induced cognitive effects. Full article

(This article belongs to the Special Issue Radiation as a Double-Edged Sword: Cancer Therapy and Potential Harm)

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13 pages, 1807 KiB

Open AccessArticle

Short Double-Stranded DNA (≤40-bp) Affects Repair Pathway Choice

by Zhentian Li and Ya Wang

Int. J. Mol. Sci. 2023, 24(14), 11836; https://doi.org/10.3390/ijms241411836 - 23 Jul 2023

Viewed by 1634

Abstract

To repair ionizing radiation (IR)-induced double strand breaks (DSBs), mammalian cells primarily use canonical non-homologous end-joining (cNHEJ), the homologous recombination (HR) pathway, and the alternative non-homologous end-joining (aEJ) as a backup. These pathways function either compensatively or competitively. High linear energy transfer (LET) compared to low-LET IR kills more cells at the same doses by inhibiting only cNHEJ, but not HR or aEJ. The mechanism remains unclear. The activation of each repair pathway requires the binding of different proteins to DNA fragments of varying lengths. We previously observed an increased generation of small DNA fragments (≤40 bp) in cells following high-LET IR compared to low-LET IR, suggesting that short DNA fragments were one of the major factors interfering with cNHEJ. To provide direct evidence, here we compare the efficiencies of cNHEJ, HR, or aEJ in repairing DSBs containing 30- or 60-bp fragments in vitro and in cells. We show that only cNHEJ but not HR or a-EJ was inefficient for repairing DSBs with 30-bp fragments compared to 60-bp ones, which strongly supports our hypothesis. These results not only enhance our understanding of the DSB repair pathway choice but also hold potential benefits for protection against high-LET IR-induced damage or improving high-LET radiotherapy. Full article

(This article belongs to the Special Issue Radiation as a Double-Edged Sword: Cancer Therapy and Potential Harm)

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