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Biology and Development of Therapeutic Drugs Targeting DNA

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 6365

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Special Issue Editors

Prof. Dr. Mitsuko Masutani

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Guest Editor

1. Department of Molecular and Genomic Biomedicine, Center for Bioinformatics and Molecular Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
2. Visiting Scientist, Central Radioisotope Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
Interests: radiation oncology; biology in anti-cancer treatment; polyADP-ribosylation; anti-tumor therapeutic; mouse; boron neutron capture therapy
Special Issues, Collections and Topics in MDPI journals

Dr. Tadayoshi Bessho

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Guest Editor

The Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-6805, USA
Interests: DNA repair/DNA damage response; nucleotide excision repair (NER); double strand break (DSB) repair; DNA interstrand cross-link (ICL) repair; DNA protein cross-link (DPC) repair; base excision repair (BER)
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

DNA-targeting drugs that directly interact with DNA, such as alkylating, crosslinking, and DNA intercalating agents have been used in cancer chemotherapies for decades with some success. Recently, drugs that selectively target DNA repair factors have been developed, with some of these drugs currently under clinical trial. DNA repair inhibitors with a selective target, such as inhibitors of poly(ADP-ribose) polymerase, indirectly introduce lethal DNA damage to cancer cells. Inhibitors of epigenetic and chromatin regulation also indirectly target DNA, causing cancer cell death. DNA targeting drugs that induce lethal DNA damage directly or indirectly will become a critical component of effective cancer chemotherapies in the future. Thus, this Special Issue will focus on the use of DNA targeting drugs, namely those that target DNA repair and epigenetic and chromatin regulation, for various diseases, including cancers. Authors are invited to submit original research articles and reviews on various types of molecular and biological aspects of DNA targeting drugs for inclusion in this Special Issue.

Dr. Mitsuko Masutani
Dr. Tadayoshi Bessho
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 targeting drugs
DNA repair/DNA damage response
molecular targeted therapy

Published Papers (4 papers)

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Research

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14 pages, 2517 KiB

Open AccessArticle

Elucidating Differences in Early-Stage Centrosome Amplification in Primary and Immortalized Mouse Cells

by Masakazu Tanaka, Masaki Yamada, Masatoshi Mushiake, Masataka Tsuda and Masanao Miwa

Int. J. Mol. Sci. 2024, 25(1), 383; https://doi.org/10.3390/ijms25010383 - 27 Dec 2023

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Abstract

The centrosome is involved in cytoplasmic microtubule organization during interphase and in mitotic spindle assembly during cell division. Centrosome amplification (abnormal proliferation of centrosome number) has been observed in several types of cancer and in precancerous conditions. Therefore, it is important to elucidate the mechanism of centrosome amplification in order to understand the early stage of carcinogenesis. Primary cells could be used to better understand the early stage of carcinogenesis rather than immortalized cells, which tend to have various genetic and epigenetic changes. Previously, we demonstrated that a poly(ADP-ribose) polymerase (PARP) inhibitor, 3-aminobenzamide (3AB), which is known to be nontoxic and nonmutagenic, could induce centrosome amplification and chromosomal aneuploidy in CHO-K1 cells. In this study, we compared primary mouse embryonic fibroblasts (MEF) and immortalized MEF using 3AB. Although centrosome amplification was induced with 3AB treatment in immortalized MEF, a more potent PARP inhibitor, AG14361, was required for primary MEF. However, after centrosome amplification, neither 3AB in immortalized MEF nor AG14361 in primary MEF caused chromosomal aneuploidy, suggesting that further genetic and/or epigenetic change(s) are required to exhibit aneuploidy. The DNA-damaging agents doxorubicin and γ-irradiation can cause cancer and centrosome amplification in experimental animals. Although doxorubicin and γ-irradiation induced centrosome amplification and led to decreased p27Kip protein levels in immortalized MEF and primary MEF, the phosphorylation ratio of nucleophosmin (Thr199) increased in immortalized MEF, whereas it decreased in primary MEF. These results suggest that there exists a yet unidentified pathway, different from the nucleophosmin phosphorylation pathway, which can cause centrosome amplification in primary MEF. Full article

(This article belongs to the Special Issue Biology and Development of Therapeutic Drugs Targeting DNA)

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17 pages, 2109 KiB

Open AccessArticle

Characterization of Systemic and Culprit-Coronary Artery miR-483-5p Expression in Chronic CAD and Acute Myocardial Infarction Male Patients

by Olga Volodko, Natalia Volinsky, Merav Yarkoni, Nufar Margalit, Fabio Kusniec, Doron Sudarsky, Gabby Elbaz-Greener, Shemy Carasso and Offer Amir

Int. J. Mol. Sci. 2023, 24(10), 8551; https://doi.org/10.3390/ijms24108551 - 10 May 2023

Cited by 1 | Viewed by 1651

Abstract

Coronary artery disease (CAD) is the leading cause of mortality worldwide. In chronic and myocardial infarction (MI) states, aberrant levels of circulating microRNAs compromise gene expression and pathophysiology. We aimed to compare microRNA expression in chronic-CAD and acute-MI male patients in peripheral blood vasculature versus coronary arteries proximal to a culprit area. Blood from chronic-CAD, acute-MI with/out ST segment elevation (STEMI/NSTEMI, respectively), and control patients lacking previous CAD or having patent coronary arteries was collected during coronary catheterization from peripheral arteries and from proximal culprit coronary arteries aimed for the interventions. Random coronary arterial blood was collected from controls; RNA extraction, miRNA library preparation and Next Generation Sequencing followed. High concentrations of microRNA-483-5p (miR-483-5p) were noted as ‘coronary arterial gradient’ in culprit acute-MI versus chronic-CAD (p = 0.035) which were similar to controls versus chronic-CAD (p < 0.001). Meanwhile, peripheral miR-483-5p was downregulated in acute-MI and chronic-CAD, compared with controls (1.1 ± 2.2 vs. 2.6 ± 3.3, respectively, p < 0.005). A receiver operating characteristic curve analysis for miR483-5p association with chronic CAD demonstrated an area under the curve of 0.722 (p < 0.001) with 79% sensitivity and 70% specificity. Using in silico gene analysis, we detected miR-483-5p cardiac gene targets, responsible for inflammation (PLA2G5), oxidative stress (NUDT8, GRK2), apoptosis (DNAAF10), fibrosis (IQSEC2, ZMYM6, MYOM2), angiogenesis (HGSNAT, TIMP2) and wound healing (ADAMTS2). High miR-483-5p ‘coronary arterial gradient’ in acute-MI, unnoticed in chronic-CAD, suggests important local mechanisms for miR483-5p in CAD in response to local myocardial ischemia. MiR-483-5p may have an important role as a gene modulator for pathologic and tissue repair states, is a suggestive biomarker, and is a potential therapeutic target for acute and chronic cardiovascular disease. Full article

(This article belongs to the Special Issue Biology and Development of Therapeutic Drugs Targeting DNA)

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21 pages, 3139 KiB

Open AccessArticle

Spectroscopic Characterization and Biological Activity of Hesperetin Schiff Bases and Their Cu(II) Complexes

by Anna Sykuła, Adriana Nowak, Eugenio Garribba, Aliaksandr Dzeikala, Magdalena Rowińska-Żyrek, Justyna Czerwińska, Waldemar Maniukiewicz and Elżbieta Łodyga-Chruścińska

Int. J. Mol. Sci. 2023, 24(1), 761; https://doi.org/10.3390/ijms24010761 - 01 Jan 2023

Cited by 4 | Viewed by 1863

Abstract

The three Schiff base ligands, derivatives of hesperetin, HHSB (N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]isonicotinohydrazide), HIN (N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]benzhydrazide) and HTSC (N-[2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chromen-4-ylidene]thiosemicarbazide) and their copper complexes, CuHHSB, CuHIN, and CuHTSC were designed, synthesized and analyzed in terms of their spectral characterization and the genotoxic activity. Their structures were established using several methods: elemental analysis, FT-IR, UV-Vis, EPR, and ESI-MS. Spectral data showed that in the acetate complexes the tested Schiff bases act as neutral tridentate ligand coordinating to the copper ion through two oxygen (or oxygen and sulphur) donor atoms and a nitrogen donor atom. EPR measurements indicate that in solution the complexes keep their structures with the ligands remaining bound to copper(II) in a tridentate fashion with (O^–, N, O_ket) or (O^–, N, S) donor set. The genotoxic activity of the compounds was tested against model tumour (HeLa and Caco-2) and normal (LLC-PK1) cell lines. In HeLa cells the genotoxicity for all tested compounds was noticed, for HHSB and CuHHSB was the highest, for HTSC and CuHTSC–the lowest. Generally, Cu complexes displayed lower genotoxicity to HeLa cells than ligands. In the case of Caco-2 cell line HHSB and HTSC induced the strongest breaks to DNA. On the other side, CuHHSB and CuHTSC induced the highest DNA damage against LLC-PK1. Full article

(This article belongs to the Special Issue Biology and Development of Therapeutic Drugs Targeting DNA)

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Review

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13 pages, 2470 KiB

Open AccessReview

Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review

by Kiyotaka Watanabe and Nobuhiko Seki

Int. J. Mol. Sci. 2024, 25(2), 752; https://doi.org/10.3390/ijms25020752 - 06 Jan 2024

Viewed by 1673

Abstract

DNA-targeted drugs constitute a specialized category of pharmaceuticals developed for cancer treatment, directly influencing various cellular processes involving DNA. These drugs aim to enhance treatment efficacy and minimize side effects by specifically targeting molecules or pathways crucial to cancer growth. Unlike conventional chemotherapeutic drugs, recent discoveries have yielded DNA-targeted agents with improved effectiveness, and a new generation is anticipated to be even more specific and potent. The sequencing of the human genome in 2001 marked a transformative milestone, contributing significantly to the advancement of targeted therapy and precision medicine. Anticipated progress in precision medicine is closely tied to the continuous development in the exploration of synthetic lethality, DNA repair, and expression regulatory mechanisms, including epigenetic modifications. The integration of technologies like circulating tumor DNA (ctDNA) analysis further enhances our ability to elucidate crucial regulatory factors, promising a more effective era of precision medicine. The combination of genomic knowledge and technological progress has led to a surge in clinical trials focusing on precision medicine. These trials utilize biomarkers for identifying genetic alterations, molecular profiling for potential therapeutic targets, and tailored cancer treatments addressing multiple genetic changes. The evolving landscape of genomics has prompted a paradigm shift from tumor-centric to individualized, genome-directed treatments based on biomarker analysis for each patient. The current treatment strategy involves identifying target genes or pathways, exploring drugs affecting these targets, and predicting adverse events. This review highlights strategies incorporating DNA-targeted drugs, such as PARP inhibitors, SLFN11, methylguanine methyltransferase (MGMT), and ATR kinase. Full article

(This article belongs to the Special Issue Biology and Development of Therapeutic Drugs Targeting DNA)

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