DNA Damage and Radiotherapy

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular Genetics and Genetic Diseases".

Deadline for manuscript submissions: closed (30 September 2023) | Viewed by 2454

Special Issue Editor


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Guest Editor
Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), German Cancer Consortium (DKTK), 45147 Essen, Germany
Interests: DSBs repair; secondary cancer; proton beam therapy

Special Issue Information

Dear Colleagues,

Radiotherapy (RT) is one of the most common and effective treatment strategies for cancer, which is effective for not only localized but also metastasis tumors. The effectiveness of RT is directly linked to the total exposure dose delivered to the tumor. In principle, any tumor can be controlled if the tumoricidal radiation dose can be delivered. However, tumors are surrounded by normal tissues that are susceptible to irradiation, and are thus injured inevitably. Therefore, side effects of variable severity would be caused, including the development of malignancies. Finally, total exposure dose determination requires a compromise between tumor control and normal tissues protection.

During RT, exposure of cells to ionizing radiation (IR) induces DNA double-strand breaks (DSBs), which are a major cause for lethal damage to the DNA of cancer cells, as well as being responsible for the induction of side effects. The risks posed by DSBs to the genome of higher eukaryotes are mitigated by a network of signaling pathways collectively termed the DNA damage response (DDR). DDR detects DSBs and coordinates a wide spectrum of cellular responses, including checkpoint activation and DSB repair. DDR signaling factors targeting to develop strategies for the better targeting of tumors, while the protection of normal tissues has become a subject of intensive research, such as the utilization and characterization of new radiation modality, the development and investigation of novel inhibitors of individual DSB repair pathways, etc. We, therefore, invite authors to submit original and review articles on these topics.

Dr. Fanghua Li
Guest Editor

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Keywords

  • radiotherapy
  • tumor control
  • normal tissue protection
  • DNA damage response (DDR)
  • radiation modality
  • novel inhibitors

Published Papers (2 papers)

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Research

16 pages, 5307 KiB  
Article
Genetic and Epigenetic Biomarkers Associated with Early Relapse in Pediatric Acute Lymphoblastic Leukemia: A Focused Bioinformatics Study on DNA-Repair Genes
by Walaa F. Albaqami, Ali A. Alshamrani, Ali A. Almubarak, Faris E. Alotaibi, Basil Jamal Alotaibi, Abdulrahman M. Alanazi, Moureq R. Alotaibi, Ali Alhoshani and Homood M. As Sobeai
Biomedicines 2024, 12(8), 1766; https://doi.org/10.3390/biomedicines12081766 - 5 Aug 2024
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Abstract
Genomic instability is one of the main drivers of tumorigenesis and the development of hematological malignancies. Cancer cells can remedy chemotherapeutic-induced DNA damage by upregulating DNA-repair genes and ultimately inducing therapy resistance. Nevertheless, the association between the DNA-repair genes, drug resistance, and disease [...] Read more.
Genomic instability is one of the main drivers of tumorigenesis and the development of hematological malignancies. Cancer cells can remedy chemotherapeutic-induced DNA damage by upregulating DNA-repair genes and ultimately inducing therapy resistance. Nevertheless, the association between the DNA-repair genes, drug resistance, and disease relapse has not been well characterized in acute lymphoblastic leukemia (ALL). This study aimed to explore the role of the DNA-repair machinery and the molecular mechanisms by which it is regulated in early- and late-relapsing pediatric ALL patients. We performed secondary data analysis on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)—ALL expansion phase II trial of 198 relapsed pediatric precursor B-cell ALL. Comprehensive genetic and epigenetic investigations of 147 DNA-repair genes were conducted in the study. Gene expression was assessed using Microarray and RNA-sequencing platforms. Genomic alternations, methylation status, and miRNA transcriptome were investigated for the candidate DNA-repair genes. We identified three DNA-repair genes, ALKBH3, NHEJ1, and PARP1, that were upregulated in early relapsers compared to late relapsers (p < 0.05). Such upregulation at diagnosis was significantly associated with disease-free survival and overall survival in precursor-B-ALL (p < 0.05). Moreover, PARP1 upregulation accompanied a significant downregulation of its targeting miRNA, miR-1301-3p (p = 0.0152), which was strongly linked with poorer disease-free and overall survivals. Upregulation of DNA-repair genes, PARP1 in particular, increases the likelihood of early relapse of precursor-B-ALL in children. The observation that PARP1 was upregulated in early relapsers relative to late relapsers might serve as a valid rationale for proposing alternative treatment approaches, such as using PARP inhibitors with chemotherapy. Full article
(This article belongs to the Special Issue DNA Damage and Radiotherapy)
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19 pages, 4798 KiB  
Article
The Combination of Radiation with PARP Inhibition Enhances Senescence and Sensitivity to the Senolytic, Navitoclax, in Triple Negative Breast Tumor Cells
by Abrar Softah, Moureq R. Alotaibi, Ali R. Alhoshani, Tareq Saleh, Khalid Alhazzani, Mashal M. Almutairi, Raed AlRowis, Samiyah Alshehri, Norah A. Albekairy, Hisashi Harada, Rowan Boyd, Eesha Chakraborty, David A. Gewirtz and Homood M. As Sobeai
Biomedicines 2023, 11(11), 3066; https://doi.org/10.3390/biomedicines11113066 - 16 Nov 2023
Cited by 1 | Viewed by 1811
Abstract
Despite significant advances in the treatment of triple-negative breast cancer, this disease continues to pose a clinical challenge, with many patients ultimately suffering from relapse. Tumor cells that recover after entering into a state of senescence after chemotherapy or radiation have been shown [...] Read more.
Despite significant advances in the treatment of triple-negative breast cancer, this disease continues to pose a clinical challenge, with many patients ultimately suffering from relapse. Tumor cells that recover after entering into a state of senescence after chemotherapy or radiation have been shown to develop a more aggressive phenotype, and to contribute to disease recurrence. By combining the PARP inhibitor (PARPi), talazoparib, with radiation, senescence was enhanced in 4T1 and MDA-MB-231 triple-negative breast cancer cell lines (based on SA-β-gal upregulation, increased expression of CDKN1A and the senescence-associated secretory phenotype (SASP) marker, IL6). Subsequent treatment of the radiation- and talazoparib-induced senescent 4T1 and MDA-MB231 cells with navitoclax (ABT-263) resulted in significant apoptotic cell death. In immunocompetent tumor-bearing mice, navitoclax exerted a modest growth inhibitory effect when used alone, but dramatically interfered with the recovery of 4T1-derived tumors induced into senescence with ionizing radiation and talazoparib. These findings support the potential utility of a senolytic strategy in combination with the radiotherapy/PARPi combination to mitigate the risk of disease recurrence in triple-negative breast cancer. Full article
(This article belongs to the Special Issue DNA Damage and Radiotherapy)
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