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DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation

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A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 17869

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Special Issue Editors

Prof. Dr. Dewei Jiang

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Guest Editor

Department of Cancer Biology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
Interests: DNA damage response; co-regulation in epigenetics and metabolism; cancer stem cells; oncolytic virus

Dr. Qi Wu

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Guest Editor

Tongji University Cancer Center, Shanghai Tenth People’s Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200072, China
Interests: tumor immunology; tumor metabolism; adenosine metabolism; immungentic cell stress; cancer-associated adipocytes

Special Issue Information

Dear Colleagues,

This Special Issue is devoted to elaborate the potential molecular mechanisms and translational research connecting DNA damage and cancer metabolism. DNA is vulnerable to damage resulting from various endogenous and exogenous phenomena including endogenous metabolites. For example, reactive oxygen species (ROS) can induce DNA damage and influence the cellular DNA damage response (DDR) signaling, especially in the context of Double Strand Breaks (DSB). Similarly, high levels of ROS stimulate glutathione synthesis to alleviate oxidative stress. Furthermore, various DNA repair pathways require specific metabolic co-substrates to maintain genomic stability. For example, Poly (ADP-ribose) polymerase 1 (PARP1) is an important mediator of DNA repair, and utilizes NAD⁺ as a co-substrate. Moreover, indirect action of metabolites in DDR via crosstalk with epigenetic regulation is also widely reported, contributing to the DNA damage repair efficiency or repair method choice. Clinically, the treatment effects of cancer therapeutics such as chemotherapy, radiotherapy, and immunotherapy are highly related to DNA damage and metabolism microenvironment.

This Special Issue, entitled “DNA damage and cancer metabolism: Basic Research to Clinical Translation”, welcomes reviews and original research as well as methodologies aiming toward formulating the fundamentals and the clinically relevant translational perspectives about DNA damage and cancer metabolism.

Prof. Dr. Dewei Jiang
Dr. Qi Wu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

DNA damage response
metabolites
DNA repair pathways
epigenetics in DDR
clinical therapeutics

Published Papers (7 papers)

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Research

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25 pages, 41269 KiB

Open AccessArticle

The Over-Irradiation Metabolite Derivative, 24-Hydroxylumister-ol₃, Reduces UV-Induced Damage in Skin

by Warusavithana Gunawardena Manori De Silva, Bianca Yuko McCarthy, Jeremy Han, Chen Yang, Andrew J. A. Holland, Harvey Stern, Katie Marie Dixon, Edith Kai Yan Tang, Robert Charles Tuckey, Mark Stephen Rybchyn and Rebecca Sara Mason

Metabolites 2023, 13(7), 775; https://doi.org/10.3390/metabo13070775 - 21 Jun 2023

Cited by 4 | Viewed by 1471

Abstract

The hormonal form of vitamin D₃, 1,25(OH)₂D₃, reduces UV-induced DNA damage. UV exposure initiates pre-vitamin D₃ production in the skin, and continued UV exposure photoisomerizes pre-vitamin D₃ to produce “over-irradiation products” such as lumisterol₃ (L₃). Cytochrome P450 side-chain cleavage enzyme (CYP11A1) in skin catalyzes the conversion of L₃ to produce three main derivatives: 24-hydroxy-L₃ [24(OH)L₃], 22-hydroxy-L₃ [22(OH)L₃], and 20,22-dihydroxy-L₃ [20,22(OH)L₃]. The current study investigated the photoprotective properties of the major over-irradiation metabolite, 24(OH)L₃, in human primary keratinocytes and human skin explants. The results indicated that treatment immediately after UV with either 24(OH)L₃ or 1,25(OH)₂D₃ reduced UV-induced cyclobutane pyrimidine dimers and oxidative DNA damage, with similar concentration response curves in keratinocytes, although in skin explants, 1,25(OH)₂D₃ was more potent. The reductions in DNA damage by both compounds were, at least in part, the result of increased DNA repair through increased energy availability via increased glycolysis, as well as increased DNA damage recognition proteins in the nucleotide excision repair pathway. Reductions in UV-induced DNA photolesions by either compound occurred in the presence of lower reactive oxygen species. The results indicated that under in vitro and ex vivo conditions, 24(OH)L₃ provided photoprotection against UV damage similar to that of 1,25(OH)₂D₃. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

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14 pages, 3294 KiB

Open AccessArticle

Chromosomal Instability Causes Sensitivity to Polyamines and One-Carbon Metabolism

by Anowarul Islam, Zeeshan Shaukat, David L. Newman, Rashid Hussain, Michael G. Ricos, Leanne Dibbens and Stephen L. Gregory

Metabolites 2023, 13(5), 642; https://doi.org/10.3390/metabo13050642 - 9 May 2023

Cited by 2 | Viewed by 1255

Abstract

Aneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift, which makes these cells sensitive to internal and environmental stresses. Using Drosophila as a model, we investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). The depletion of several of these genes has led to cell death by apoptosis in CIN cells but not in normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by the loss of SAM synthase in CIN tissues. The loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown to contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention such as polyamine inhibition has the potential to target CIN tumours via a relatively well-characterised mechanism. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

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Graphical abstract

20 pages, 5955 KiB

Open AccessArticle

Identification of Lignan Compounds as New 6-Phosphogluconate Dehydrogenase Inhibitors for Lung Cancer

by Gul Bushra Khan, Muhammad Qasim, Azhar Rasul, Usman Ali Ashfaq and Abdullah M. Alnuqaydan

Metabolites 2023, 13(1), 34; https://doi.org/10.3390/metabo13010034 - 24 Dec 2022

Cited by 3 | Viewed by 2938

Abstract

Targeting pentose phosphate pathway (PPP) enzymes has emerged as a promising strategy to combat cancer. 6-Phosphogluconate dehydrogenase (6-PGD), the third critical enzyme of the PPP, catalyzes oxidative decarboxylation of 6-phosphogluconate (6-PG) to produce ribulose-5-phosphate (Ru-5-P) and CO2. Overexpression of 6-PGD has been reported in multiple cancers and is recognized as a potential anticancer drug target. The current study is focused on the utilization of indispensable virtual screening tools for structure-based drug discovery. During the study, 17,000 natural compounds were screened against the 3-phosphoglycerate (3-PG) binding site of 6-PGD through a molecular operating environment (MOE), which revealed 115 inhibitors with higher selectivity and binding affinity. Out of the 115 best-fit compounds within the 6-PGD binding cavity, 15 compounds were selected and optimized through stringent in silico ADMET assessment models that justified the desirable pharmacokinetic, pharmacodynamic and physicochemical profiles of 5 ligands. Further protein–ligand stability assessment through molecular dynamics (MD) simulation illustrated three potential hits, secoisolariciresinol, syringaresinol and cleomiscosin A, with stable confirmation. Moreover, 6-PGD inhibitor validation was performed by an in vitro enzymatic assay using human erythrocytes purified 6-PGD protein and A549 cell lysate protein. The results of the in vitro assays supported the in silico findings. In order to gain insight into the anticancer activity of the aforementioned compounds, they were subjected to CLC-Pred, an in silico cytotoxicity browsing tool, which proved their anticancer activity against several cancer cell lines at Pa > 0.5. Additionally, a confirmation for in silico cytotoxicity was made by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for commercially available hits syringaresinol and cleomiscosin A against lung cancer (A549) cells. The results demonstrated that syringaresinol has an IC₅₀ value of 36.9 μg/mL, while cleomiscosin A has an IC₅₀ value of 133 μg/mL. After MTT, flow cytometry analysis confirmed that compounds induced apoptosis in A549 cells in a dose-dependent manner. This study suggested that the respective lignan compounds can serve as lead candidates for lung cancer therapy via 6-PGD inhibition. Furthermore, in vivo experiments need to be conducted to confirm their efficacy. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

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Review

Jump to: Research

24 pages, 2560 KiB

Open AccessReview

Cancer Metabolism: The Role of ROS in DNA Damage and Induction of Apoptosis in Cancer Cells

by Yongxia Zhao, Xiaochun Ye, Zhifeng Xiong, Awais Ihsan, Irma Ares, Marta Martínez, Bernardo Lopez-Torres, María-Rosa Martínez-Larrañaga, Arturo Anadón, Xu Wang and María-Aránzazu Martínez

Metabolites 2023, 13(7), 796; https://doi.org/10.3390/metabo13070796 - 27 Jun 2023

Cited by 13 | Viewed by 2996

Abstract

Cancer is a huge challenge for people worldwide. High reactive oxygen species (ROS) levels are a recognized hallmark of cancer and an important aspect of cancer treatment research. Abnormally elevated ROS levels are often attributable to alterations in cellular metabolic activities and increased oxidative stress, which affects both the development and maintenance of cancer. Moderately high levels of ROS are beneficial to maintain tumor cell genesis and development, while toxic levels of ROS have been shown to be an important force in destroying cancer cells. ROS has become an important anticancer target based on the proapoptotic effect of toxic levels of ROS. Therefore, this review summarizes the role of increased ROS in DNA damage and the apoptosis of cancer cells caused by changes in cancer cell metabolism, as well as various anticancer therapies targeting ROS generation, in order to provide references for cancer therapies based on ROS generation. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

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17 pages, 678 KiB

Open AccessEditor’s ChoiceReview

Targeting Both Autophagy and Immunotherapy in Breast Cancer Treatment

by Spyridon Giannopoulos, Cansu Cimen Bozkus, Eleni Zografos, Aikaterini Athanasiou, Ann Marie Bongiovanni, Georgios Doulaveris, Chris N. Bakoyiannis, Georgios E. Theodoropoulos, Georgios C. Zografos, Steven S. Witkin and Theofano Orfanelli

Metabolites 2022, 12(10), 966; https://doi.org/10.3390/metabo12100966 - 12 Oct 2022

Cited by 4 | Viewed by 2321

Abstract

As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

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32 pages, 1957 KiB

Open AccessReview

Novel Implications of Nanoparticle-Enhanced Radiotherapy and Brachytherapy: Z-Effect and Tumor Hypoxia

by Runze Zhou, Di Zhao, Narasimha M. Beeraka, Xiaoyan Wang, Pengwei Lu, Ruixia Song, Kuo Chen and Junqi Liu

Metabolites 2022, 12(10), 943; https://doi.org/10.3390/metabo12100943 - 5 Oct 2022

Cited by 8 | Viewed by 3376

Abstract

Radiotherapy and internal radioisotope therapy (brachytherapy) induce tumor cell death through different molecular signaling pathways. However, these therapies in cancer patients are constrained by dose-related adverse effects and local discomfort due to the prolonged exposure to the surrounding tissues. Technological advancements in nanotechnology have resulted in synthesis of high atomic elements such as nanomaterials, which can be used as radiosensitizers due to their photoelectric characteristics. The aim of this review is to elucidate the effects of novel nanomaterials in the field of radiation oncology to ameliorate dose-related toxicity through the application of ideal nanoparticle-based radiosensitizers such as Au (gold), Bi (bismuth), and Lu (Lutetium-177) for enhancing cytotoxic effects of radiotherapy via the high-Z effect. In addition, we discuss the role of nanoparticle-enhanced radiotherapy in alleviating tumor hypoxia through the nanodelivery of genes/drugs and other functional anticancer molecules. The implications of engineered nanoparticles in preclinical and clinical studies still need to be studied in order to explore potential mechanisms for radiosensitization by minimizing tumor hypoxia, operational/logistic complications and by overcoming tumor heterogeneity in radiotherapy/brachytherapy. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

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19 pages, 1700 KiB

Open AccessReview

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

by Sirui Chen, Jingjing Jiang, Ao Shen, Ying Miao, Yunfeng Cao, Ying Zhang, Peiyu Cong and Peng Gao

Metabolites 2022, 12(10), 918; https://doi.org/10.3390/metabo12100918 - 28 Sep 2022

Cited by 3 | Viewed by 2587

Abstract

Amino acids (AAs) are indispensable building blocks of diverse bio-macromolecules as well as functional regulators for various metabolic processes. The fact that cancer cells live with a voracious appetite for specific AAs has been widely recognized. Glioma is one of the most lethal malignancies occurring in the central nervous system. The reprogrammed metabolism of AAs benefits glioma proliferation, signal transduction, epigenetic modification, and stress tolerance. Metabolic alteration of specific AAs also contributes to glioma immune escape and chemoresistance. For clinical consideration, fluctuations in the concentrations of AAs observed in specific body fluids provides opportunities to develop new diagnosis and prognosis markers. This review aimed at providing an extra dimension to understanding glioma pathology with respect to the rewired AA metabolism. A deep insight into the relevant fields will help to pave a new way for new therapeutic target identification and valuable biomarker development. Full article

(This article belongs to the Special Issue DNA Damage and Cancer Metabolism: Basic Research to Clinical Translation)

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