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Special Issue "Radiation-Induced Damage to DNA"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: 30 September 2019.

Special Issue Editors

Guest Editor
Prof. Dr. Janusz Rak Website E-Mail
Department of Physical Chemistry, Uniwersytet Gdanski, Gdańsk, Poland
Interests: radiation chemistry; photochemistry; quantum-chemistry; DNA damage
Guest Editor
Dr. Magdalena Zdrowowicz Website E-Mail
Department of Physical Chemistry, Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Interests: radiosensitizers; photosensitizers; DNA damage; PCR; cellular studies

Special Issue Information

Dear Colleague,

Since cancer is the third leading cause of death, radiation-induced damage to DNA is a topic of a paramount importance. Indeed, radiotherapy and photodynamic therapy are common modalities for treating human cancers, and causing efficient damage to the DNA of tumor cells is their main target. The efficacy of the above-mentioned modalities is a serious issue, since solid tumors, which account for c. 80% of cases, are hypoxic, which significantly reduces the extent of primary damage induced either by the ionizing or UV photons.

This Special issue will expose the reader to: the mechanisms of direct and indirect radiation-induced DNA damage, radiation damage to DNA–protein complexes, the computational modeling of radiation damage to DNA, radio- and photosensitizers of DNA damage, repair of radiation-induced DNA damage, the biological consequences of DNA damage, the radiotherapy of cancer, photodynamic therapy, and cellular responses to DNA damage.

The gathered SI articles are expected to provide a reference for recent development in this interdisciplinary and practical subject, with anticancer therapy as a hallmark, to organic and medicinal chemists, radiation and photochemists, molecular modeling chemists, as well as cellular biologists who are in the target audience.

Prof. Dr. Janusz Rak
Dr. Magdalena Zdrowowicz
Guest Editors

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

  • DNA radio-/photodamage
  • Radiosensitizers
  • Solvated electrons
  • Photosensitizers
  • Hypoxia
  • DNA repair
  • Protein–DNA complexes
  • Molecular modeling of DNA damage

Published Papers (5 papers)

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Research

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Open AccessArticle
Ring Formation and Hydration Effects in Electron Attachment to Misonidazole
Int. J. Mol. Sci. 2019, 20(18), 4383; https://doi.org/10.3390/ijms20184383 - 06 Sep 2019
Abstract
We study the reactivity of misonidazole with low-energy electrons in a water environment combining experiment and theoretical modelling. The environment is modelled by sequential hydration of misonidazole clusters in vacuum. The well-defined experimental conditions enable computational modeling of the observed reactions. While the [...] Read more.
We study the reactivity of misonidazole with low-energy electrons in a water environment combining experiment and theoretical modelling. The environment is modelled by sequential hydration of misonidazole clusters in vacuum. The well-defined experimental conditions enable computational modeling of the observed reactions. While the NO 2 dissociative electron attachment channel is suppressed, as also observed previously for other molecules, the OH channel remains open. Such behavior is enabled by the high hydration energy of OH and ring formation in the neutral radical co-fragment. These observations help to understand the mechanism of bio-reductive drug action. Electron-induced formation of covalent bonds is then important not only for biological processes but may find applications also in technology. Full article
(This article belongs to the Special Issue Radiation-Induced Damage to DNA)
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Open AccessArticle
Reactions in the Radiosensitizer Misonidazole Induced by Low-Energy (0–10 eV) Electrons
Int. J. Mol. Sci. 2019, 20(14), 3496; https://doi.org/10.3390/ijms20143496 - 16 Jul 2019
Cited by 1
Abstract
Misonidazole (MISO) was considered as radiosensitizer for the treatment of hypoxic tumors. A prerequisite for entering a hypoxic cell is reduction of the drug, which may occur in the early physical-chemical stage of radiation damage. Here we study electron attachment to MISO and [...] Read more.
Misonidazole (MISO) was considered as radiosensitizer for the treatment of hypoxic tumors. A prerequisite for entering a hypoxic cell is reduction of the drug, which may occur in the early physical-chemical stage of radiation damage. Here we study electron attachment to MISO and find that it very effectively captures low energy electrons to form the non-decomposed molecular anion. This associative attachment (AA) process is exclusively operative within a very narrow resonance right at threshold (zero electron energy). In addition, a variety of negatively charged fragments are observed in the electron energy range 0–10 eV arising from dissociative electron attachment (DEA) processes. The observed DEA reactions include single bond cleavages (formation of NO2), multiple bond cleavages (excision of CN) as well as complex reactions associated with rearrangement in the transitory anion and formation of new molecules (loss of a neutral H2O unit). While any of these AA and DEA processes represent a reduction of the MISO molecule, the radicals formed in the course of the DEA reactions may play an important role in the action of MISO as radiosensitizer inside the hypoxic cell. The present results may thus reveal details of the molecular description of the action of MISO in hypoxic cells. Full article
(This article belongs to the Special Issue Radiation-Induced Damage to DNA)
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Open AccessArticle
5-Iodo-4-thio-2′-Deoxyuridine as a Sensitizer of X-ray Induced Cancer Cell Killing
Int. J. Mol. Sci. 2019, 20(6), 1308; https://doi.org/10.3390/ijms20061308 - 15 Mar 2019
Cited by 1
Abstract
Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2′-deoxyuridine (ISdU) as a compound that can effectively [...] Read more.
Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2′-deoxyuridine (ISdU) as a compound that can effectively lead to ionizing radiation (IR)-induced cellular death, which is proven by a clonogenic assay. The test revealed that the survival of cells, pre-treated with 10 or 100 µM solution of ISdU and exposed to 0.5 Gy of IR, was reduced from 78.4% (for non-treated culture) to 67.7% and to 59.8%, respectively. For a somewhat higher dose of 1 Gy, the surviving fraction was reduced from 68.2% to 54.9% and to 40.8% for incubation with 10 or 100 µM ISdU, respectively. The cytometric analysis of histone H2A.X phosphorylation showed that the radiosensitizing effect of ISdU was associated, at least in part, with the formation of double-strand breaks. Moreover, the cytotoxic test against the MCF-7 breast cancer cell line and human dermal fibroblasts (HDFa line) confirmed low cytotoxic activity of ISdU. Based on the results of steady state radiolysis of ISdU with a dose of 140 Gy and quantum chemical calculations explaining the origin of the MS detected radioproducts, the molecular mechanism of sensitization by ISdU was proposed. In conclusion, we found ISdU to be a potential radiosensitizer that could improve anticancer radiotherapy. Full article
(This article belongs to the Special Issue Radiation-Induced Damage to DNA)
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Review

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Open AccessReview
Reaction of Electrons with DNA: Radiation Damage to Radiosensitization
Int. J. Mol. Sci. 2019, 20(16), 3998; https://doi.org/10.3390/ijms20163998 - 16 Aug 2019
Abstract
This review article provides a concise overview of electron involvement in DNA radiation damage. The review begins with the various states of radiation-produced electrons: Secondary electrons (SE), low energy electrons (LEE), electrons at near zero kinetic energy in water (quasi-free electrons, (e [...] Read more.
This review article provides a concise overview of electron involvement in DNA radiation damage. The review begins with the various states of radiation-produced electrons: Secondary electrons (SE), low energy electrons (LEE), electrons at near zero kinetic energy in water (quasi-free electrons, (eqf)) electrons in the process of solvation in water (presolvated electrons, epre), and fully solvated electrons (eaq). A current summary of the structure of eaq, and its reactions with DNA-model systems is presented. Theoretical works on reduction potentials of DNA-bases were found to be in agreement with experiments. This review points out the proposed role of LEE-induced frank DNA-strand breaks in ion-beam irradiated DNA. The final section presents radiation-produced electron-mediated site-specific formation of oxidative neutral aminyl radicals from azidonucleosides and the evidence of radiosensitization provided by these aminyl radicals in azidonucleoside-incorporated breast cancer cells. Full article
(This article belongs to the Special Issue Radiation-Induced Damage to DNA)
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Open AccessReview
Clustered DNA Damages induced by 0.5 to 30 eV Electrons
Int. J. Mol. Sci. 2019, 20(15), 3749; https://doi.org/10.3390/ijms20153749 - 31 Jul 2019
Abstract
Low-energy electrons (LEEs) of energies ≤30 eV are generated in large quantities by ionizing radiation. These electrons can damage DNA; particularly, they can induce the more detrimental clustered lesions in cells. This type of lesions, which are responsible for a large portion of [...] Read more.
Low-energy electrons (LEEs) of energies ≤30 eV are generated in large quantities by ionizing radiation. These electrons can damage DNA; particularly, they can induce the more detrimental clustered lesions in cells. This type of lesions, which are responsible for a large portion of the genotoxic stress generated by ionizing radiation, is described in the Introduction. The reactions initiated by the collisions of 0.5–30 eV electrons with oligonucleotides, duplex DNA, and DNA bound to chemotherapeutic platinum drugs are explained and reviewed in the subsequent sections. The experimental methods of LEE irradiation and DNA damage analysis are described with an emphasis on the detection of cluster lesions, which are considerably enhanced in DNA–Pt–drug complexes. Based on the energy dependence of damage yields and cross-sections, a mechanism responsible for the clustered lesions can be attributed to the capture of a single electron by the electron affinity of an excited state of a base, leading to the formation of transient anions at 6 and 10 eV. The initial capture is followed by electronic excitation of the base and dissociative attachment—at other DNA sites—of the electron reemitted from the temporary base anion. The mechanism is expected to be universal in the cellular environment and plays an important role in the formation of clustered lesions. Full article
(This article belongs to the Special Issue Radiation-Induced Damage to DNA)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Damage induced to DNA by 1-30 eV electrons
Authors: Leon Sanche
Summary: My intention is to limit the article to a review of reactions  initiated by the collisions of 1-30 eV electrons with  duplex DNA and oligonucleotides. These reactions will be described along with their mechanisms of action (e.g., transient anions localized on the molecular subunits of DNA). The experimental methods as well as the experimental results will be reviewed.

Title: Micronucleus assay: current chellenges and future directions
Authors: Marcin Kruszewski
Abstract: During almost 40 years of its use, micronucleus assay became one of the most popular method to assess genotoxicity, including radiation induced DNA damage.  In this minireview we focused on problems with the assay implementation that arose during these years and were still unsolved. In addition, a foreseen application of the assay in genotoxicity testing will be discuss in regards to radiobiology and health protection.

Title: Reactions in the Radiosensitiser Misonidazole Induced by Low-Energy (0-10 eV) Electrons
Authors: Stephan Denifl and coworkers
Summary: The nitroimidazolic compound misonidazole was considered as radiosensitiser for the treatment of hypoxic tumors. In this research article we present the results from our recent electron attachment studies with this radiosensitiser. A crossed beam apparatus was employed to monitor (fragment) anions formed upon the low-energy attachment reactions.

Title: Radiation-induced Formation of DNA-radicals and Their Reactions: A Current Perspective from Experiment and Theory
Authors: David Becker, Anil Kumar, Amitava Adhikary, and Michael Sevilla
Summary: This review will describe the pathways of formation and fates of various DNA-radicals formed via low LET (e.g., -γ) and a variety of high LET (ion-beam) radiations and indicate how these processes lead to a radiation chemical track structure model that is being developed in our laboratory to account for the ion-beam radiation-induced damage in DNA. This review will also summarize the current status of theoretical works on redox potentials of various DNA-radicals, including on the reduction potentials of DNA-anion radials formed by addition of solvated (or, aqueous) electrons with DNA-models.

Title: Probing Radiation-produced Excess Electron-mediated DNA Damage Pathways in Solution at Room Temperature
Authors: Jun Ma, Sergey A. Denisov, Amitava Adhikary, and Mehran Mostafavi
Summary: Radiation-produced electrons in various solvation states (quasi-free, presolvated, and solvated) add to DNA-models to produce anion radicals (or, the transient negative ions (TNIs)). Analyzing the product of these reactions with the aid of ultrafast pulse radiolysis technique at room temperature, we find that only addition of quasi-free electrons to DNA-models produce damage through N1-C1’ glycosidic bond cleavage. Dissociative electron attachment mechanism of the TNI in its excited state is proposed to explain this damage.

Title: In situ analysis of DNA-protein complex formation upon radiation-induced DNA damage
Author: Ennio Prosperi
Short Abstract: The importance of determining at cellular level the formation of DNA-protein complexes after radiation-induced lesions to DNA, is outlined by the fact that such complexes represents one of the first steps of the cellular response to DNA damage. These complexes arise by recruitment at the sites of the lesion, of proteins to signal the presence of DNA damage, and of DNA repair factors. Investigating their formation may provide relevant information about molecular mechanisms and spatio-temporal dynamics of these important cellular pathways.

Title: Length and Energy Dependence of Low-Energy Electron-induced Strand Breaks in Adenine-containing ssDNA
Authors: Kenny Ebel and Ilko Bald*
Affiliation: Department 1 – Analytical Chemistry and Reference Materials, BAM Federal Institute for Materials Research and Testing, Richard-Willstätter-Str. 11, 12487 Berlin
Institute of Chemistry – Physical Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, 14476 Potsdam, Germany
*[email protected]
Abstract: The DNA in living cells can be effectively damaged by everyday radiation which can lead to cancer or apoptosis (cell death). Latter effect is used in cancer radiation therapy where high-energy radiation can kill cancer tissues. Highly reactive secondary species such as low-energy electrons (LEE) with an energy maximum at around 10 eV are generated through the ionization of water molecules. The LEEs can induce DNA strand breaks at specific energies via dissociative electron attachment (DEA)involving negative ion resonances. Using triangular DNA origami nanostructures, we can determine absolute DNA strand break cross sections on a molecular level. It was suggested that DNA strand breaks strongly depend on the specific DNA length and irradiation energy. The present work shows results for adenine rich DNA (d-A4, d-A8, d-A12, d-A16 and d-A20) irradiated at 5.0, 7.0, 8.4 and 10 eV. In contrast to the geometrical cross sections, no linear increase of DNA strand break cross sections with DNA length is observed, i.e. there is no direct correlation between DNA length and LEE induced strand break cross section. The highest cross section is determined for d-A12. Independent of the length of the DNA sequences, all oligonucleotides show a resonance at 7 eV electron energy.

Title: A pro forma quantification of radiation-induced damage to bio-cells
Author: Hiroyuki Date
Abstract: In this study, we attempt to parametrize the radiation-induced damage by means of non-lethal probability (NLP) model resting on the target theory. The model  is applied to the experimental survival data of the cells exposed to X- and gamma-rays. We estimate the degree of damage and its repair probability by taking account of the cell survival data for a variety of repairing time condition.

Title: Radio-enhancing properties of bimetallic Au:Pt nanoparticles: experimental and theoretical evidence
Authors: Daniela Salado-Leza 1,2, Ali Traore 3, Erika Porcel 1, Diana Dragoe 4, Antonio Muñoz 5, Hynd Remita 6, Gustavo García 3 and Sandrine Lacombe 1*
Affiliations: 1Institut des Sciences Moléculaires d’Orsay (UMR 8214) Univ. Paris-Sud, Université Paris-Saclay, CNRS, 91405 Orsay, France; 2Cátedras CONACyT, Universidad Autónoma de San Luis Potosí, Facultad de Ciencias Químicas, Av. Dr. Manuel Nava 6, Zona Universitaria, 78210 San Luis Potosí, S.L.P., Mexico; 3Instituto de Física Fundamental, Consejo Superior de Investigaciones Científicas (CSIC), Serrano 113-bis, 28006 Madrid, Spain; 4Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), UMR 8182 CNRS, Université Paris Saclay, Univ. Paris Sud, 91405 Orsay, France; 5Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas (CIEMAT), Avda. Complutense 22, 28040 Madrid, Spain; 6Laboratoire de Chimie Physique (LCP), UMR 8000 CNRS, Université Paris Saclay, Univ. Paris-Sud,  91405 Orsay, France.
Abstract: The use of nanoparticles in combination with ionizing radiation is considered as a promising method to improve the performance of radiation therapies. Monometallic gold nanoparticles are the most popular agents within this concern. In this work, we engineered mono- and bimetallic core-shell gold-platinum nanoparticles grafted with poly (ethylene glycol). The radio-enhancing properties of nanoparticles were investigated using plasmids as nano-biomolecular probes. Gamma rays delivered by a 60Co source were used as ionizing radiation. We found that the presence of bimetallic gold-platinum nanoparticles increased by 90% the induction of double strand breaks, a signature of the amplification of nanosize damage, the most difficult for the cells to repair. The radio-enhancing property of bimetallic gold-platinum nanoparticles was found 3 times higher than the one of monometallic gold nanoparticles. This effect was scavenged by 80% in the presence of dimethyl sulfoxide, which demonstrates the major role of hydroxyl radicals in the induction of nanosize damage. Geant4-DNA Monte Carlo simulation was used to elucidate the physical processes involved in the radio-enhancement effect: elastic scattering, electronic excitation, vibrational excitation, ionization and molecular attachment. Taking into account these processes only (without the stage of radical chemistry), we predicted enhancement factors of 40 and 45% (standard deviation below ≤1%) for the induction of nanosize damage in the presence of mono- and bimetallic nanoparticles, respectively. This difference is attributed to secondary electron impact processes. This work contributes to a better understanding of the interplay between energy deposition and the induction of nanosize biomolecular damage. The quantification of nanosize damage using Monte Carlo simulations is a simple method to guide the synthesis of new radio-enhancing nanoparticles.
Keywords: Core-shell gold-platinum nanoparticles, radio-enhancement, radiosensitization, complex damage, Geant4-DNA, Monte Carlo

Title: Ring Formation and Hydration Effects in Electron Attachment to Misonidazole
Author: Jaroslav Kočišek
Abstract: We experimentally and theoretically examine electron attachment to Misonidazole at well-defined hydration conditions in clusters. Water environment influences dissociative electron attachment by depletion of NO_2^- reaction channel and increase of OH^- reaction channel. The increase is enabled by bond formation induced by electron attachment and high solvation energy of OH^- in water.

Title: The role of electron-transfer in the fragmentation of phenyl and cyclohexyl boronic acids 
Authors: 1. Mendes 1,2, B. Pamplona 1, J. Pereira da Silva 1, G. García 2, P. Góis 3, F. Ferreira da Silva 1 and P. Limão-Vieira 1,* 
Affiliations: 1Atomic and Molecular Collisions Laboratory, CEFITEC, Department of Physics, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
2Instituto de Física Fundamental, Consejo Superior de Investigaciones Científicas (CSIC), Serrano 113-bis, 28006 Madrid, Spain
3 Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649‐003 Lisbon (Portugal) 
* corresponding author: Paulo Limão-Vieira; [email protected]
Abstract: Negative ion formation in neutral potassium- neutral boronic acids collisions is reported for the first time in electron transfer experiments. The fragmentation pattern of phenylboronic acid is comprehensively investigated in a wide range of collision energies, i.e. from 10 up to 1000 eV in the laboratory frame, allowing to probe some of the most relevant dissociation channels . These  studies were performed in a crossed molecular beam set up using a potassium atom as an electron donor. The negative ions formed in the collision region were mass analysed with a reflectron time-of-flight mass spectrometer. In the unimolecular decomposition of the temporary negative ion, the two most relevant yields were assigned to BO and BO2. Moreover, the collision induced reaction was shown to be selective, i.e. at energies below 100 eV it is mostly formed BO, while at energies above 100 eV it is mostly formed BO2. In order to further our knowledge of the complex internal reaction mechanisms on the influence of the hybridization state of the boron atom, cyclohexylboronic acid has also investigated in the same collision energy range where the main dissociation channel yields BO2.

Title: Electron-transfer-induced decomposition of nitroimidazoles: experimental and theoretical methods 
Authors: Mendes1,2, G. García2, M.-C. Bacchus-Montabonel3,* and P. Limão-Vieira1,* 
Affiliations: 1Atomic and Molecular Collisions Laboratory, CEFITEC, Department of Physics, Universidade NOVA de Lisboa, 2829-516 Caparica, Portugal
2Instituto de Física Fundamental, Consejo Superior de Investigaciones Científicas (CSIC), Serrano 113-bis, 28006 Madrid, Spain
3 Univ. Lyon, Université Claude Bernard Lyon 1, CNRS, Institut Lumière Matière, 69622 Villeurbanne, France 
* Correspondence: Paulo Limão-Vieira; [email protected]
Abstract: We report on a combined experimental and theoretical study of electron-transfer-induced decomposition of nitroimidazole and a selection of analogue molecules in collisions with potassium (K) atoms. In this collision regime, negative ions formed by electron transfer from the alkali atom to the target molecule were time-of-flight mass analysed and the fragmentation patterns and branching ratios have been obtained. The most abundant anions have been assigned to the parent molecule and NO2 and the electron transfer mechanisms are comprehensively discussed. Following our recent work about selective hydrogen loss from the transient negative ions (TNIs) produced in these collisions [M. Mendes et al., J. Phys. Chem. A 123, 4068 (2019)], this work focuses on the production of all fragment anions produced. Particular importance is also given to the efficient loss of integrity of the nitroimidazolic ring in the presence of an extra electron, which is in contrast to dissociative electron attachment experiments. Ab initio theoretical calculations were performed for 4(5)-nitroimidazole (4(5)NI), 2-nitroimidazole, 1-methyl-4 (Me4NI) and 1-methyl-5 nitroimidazole (Me5NI) and imidazole (IMI) in the presence of a potassium atom and provided a strong basis for the assignment of the lowest unoccupied molecular orbitals accessed in the collision process.

Title: Melatonin as a radio-sensitizer in breast cancer
AuthorCarolina Alonso González
Short summary: Melatonin is a natural hormone with a broad spectrum of antitumoral actions in several types of cancers and more recently it has been demonstrated its ability to diminish DNA-damage to the normal tissue, and decreasing the DNA-repair mechanisms to cancer cells, leading to apoptosis. Thus, it seems that, in the future, melatonin may be used as a new agent to improve the efficacy of radiation oncology treatments.

Title: A potential new role of ATM inhibitor in radiotherapy: suppressing ionizing radiation-activated EGFR
Authors: Siyuan Tang, M.D.1, Zhentian Li, M.D., PhD.,2, Liangfang Shen, M.D.1* and Ya Wang, PhD.2*
Affiliations: 1Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
2Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, GA, United States
Abstract: Epidermal growth factor receptor (EGFR) is known as one of the most important tyrosine kinases and plays an oncogene role in many tumors by promoting tumor cell growth and resistance to treatment including radiotherapy. Although EGFR inhibitors have been used to treat many types of cancer, resistance to EGFR inhibitors frequently develops, which significantly reduces the treatment outcome. Recently, we reported that an ATM inhibitor efficiently abolished ionizing radiation (IR)-induced EGFR phosphorylation in mouse embryo fibroblast (MEF) although an EGFR inhibitor could not affect ATM phosphorylation status. These results indicate that ATM is an upstream regulator of EGFR and suggest that an ATM inhibitor could overcome tumor cell resistance to EGFR inhibition. The main purpose of this study is to test this hypothesis in human tumor cell lines. Here we showed that inhibition of ATM did efficiently abolish IR-induced EGFR phosphorylation in all eight tumor-cell lines tested. We also showed that inhibition of EGFR or ATM suppressed the tumor cell growth or sensitized the tumor cells to IR at a similar level but inhibition of both EGFR and ATM did not further increase the effects. Since homologous recombination (HR) and non-homologous end-joining (NHEJ) are two major double strand break (DSB) repair pathways in mammalian cells, we next examined the effects of EGFR and/or ATM inhibition on affecting which pathway, HR, NHEJ or both. Using the reporter cells that integrated the cassette containing I-Sce-I digested sequence for detecting HR or NHEJ efficiency, we showed that similar to ATM inhibition, EGFR inhibition mainly reduced HR efficiency but had fewer effects on NHEJ, inhibition of both ATM and NHEJ did not further increase the effects. Taken together, our results demonstrate that an ATM inhibitor could be an efficient alternative approach to overcome the resistance of tumor cells to an EGFR inhibitor and thus improve radiotherapy.
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