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DNA Damage Induced by Anti-cancer Agents
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DNA Damage Induced by Anti-cancer Agents

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 7637

Special Issue Editor

Dr. Colin Campbell

E-Mail Website
Guest Editor
Department of Pharmacology, University of Minnesota System, Minneapolis, MN 55455, USA
Interests: DNA repair; molecular genetics; DNA damage response

Special Issue Information

Dear Colleagues,

A decades-long focus on understanding the molecular mechanisms responsible for neoplasia has led to the development of so-called targeted anticancer therapeutics. These newer agents, including protein tyrosine kinase inhibitors, monoclonal antibodies, and immune checkpoint inhibitors, can dramatically alter the therapeutic landscape of cancer chemotherapy. Nevertheless, traditional cytotoxic anticancer drugs, and in particular DNA-damaging agents, continue to represent mainstays in the treatment of cancer. The drugs that comprise this large class utilize a variety of chemical mechanisms to induce damage in chromosomal DNA, including breaks in single and double DNA strands, chemical modifications, such as monoadducts, DNA–DNA and DNA–protein cross-links, and single-strand and double-strand breaks. This damage activates cell death in cancer cells; however, DNA damage caused by these agents in noncancer cells is responsible for adverse drug effects, including myelosuppression, secondary malignancies, and other organ-specific toxicities. In this Special Issue, we will review the current insight into the mechanisms through which these important therapeutic agents induce cellular DNA alteration. We will also discuss the cellular response to this drug-induced DNA damage, with a particular emphasis on mechanisms of DNA repair/DNA damage removal.

Dr. Colin Campbell
Guest Editor

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. Genes 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 2600 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

  • cancer chemotherapy
  • DNA repair
  • DNA damage response
  • programmed cell death
  • secondary malignancy
  • bis-electrophile
  • alkylating agent
  • antitumor antibiotics
  • topoisomerase inhibitor

Published Papers (5 papers)

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Research

Jump to: Review

15 pages, 2959 KiB  
Article
Usnic Acid Derivatives Inhibit DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 and Act as Potential Anticancer Agents
by Alexandra L. Zakharenko, Nadezhda S. Dyrkheeva, Olga A. Luzina, Aleksandr S. Filimonov, Evgenii S. Mozhaitsev, Anastasia A. Malakhova, Sergey P. Medvedev, Suren M. Zakian, Nariman F. Salakhutdinov and Olga I. Lavrik
Genes 2023, 14(10), 1931; https://doi.org/10.3390/genes14101931 - 12 Oct 2023
Viewed by 988
Abstract
Tyrosyl-DNA phosphodiesterase 1 and 2 (Tdp1 and Tdp2) are DNA repair enzymes that repair DNA damage caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reason for resistance to such widely used drugs such as [...] Read more.
Tyrosyl-DNA phosphodiesterase 1 and 2 (Tdp1 and Tdp2) are DNA repair enzymes that repair DNA damage caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reason for resistance to such widely used drugs such as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (−)-usnic acid. Both (+)- and (−)-enantiomers of compounds act equally effectively against Tdp1 with IC50 values in the range of 0.02–0.2 μM; only (−)-enantiomers inhibited Tdp2 with IC50 values in the range of 6–9 μM. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide (CC50 3.0–3.9 μM in the presence of compounds and 2.4 μM the presence of DMSO) but potentiate it against Tdp2 knockout cells (CC50 1.2–1.6 μM in the presence of compounds against 2.3 μM in the presence of DMSO). We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with the effective inhibition of Tdp1, which could take over the functions of Tdp2. Full article
(This article belongs to the Special Issue DNA Damage Induced by Anti-cancer Agents)
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12 pages, 3275 KiB  
Article
Histone Deacetylases (HDAC) Inhibitor—Valproic Acid Sensitizes Human Melanoma Cells to Dacarbazine and PARP Inhibitor
by Małgorzata Drzewiecka, Anna Gajos-Michniewicz, Grażyna Hoser, Dominika Jaśniak, Gabriela Barszczewska-Pietraszek, Przemysław Sitarek, Piotr Czarny, Janusz Piekarski, Maciej Radek, Małgorzata Czyż, Tomasz Skorski and Tomasz Śliwiński
Genes 2023, 14(6), 1295; https://doi.org/10.3390/genes14061295 - 20 Jun 2023
Cited by 3 | Viewed by 1795
Abstract
The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class [...] Read more.
The inhibition of histone deacetylases (HDACs) holds promise as a potential anti-cancer therapy as histone and non-histone protein acetylation is frequently disrupted in cancer, leading to cancer initiation and progression. Additionally, the use of a histone deacetylase inhibitor (HDACi) such as the class I HDAC inhibitor—valproic acid (VPA) has been shown to enhance the effectiveness of DNA-damaging factors, such as cisplatin or radiation. In this study, we found that the use of VPA in combination with talazoparib (BMN-673—PARP1 inhibitor—PARPi) and/or Dacarbazine (DTIC—alkylating agent) resulted in an increased rate of DNA double strand breaks (DSBs) and reduced survival (while not affecting primary melanocytes) and the proliferation of melanoma cells. Furthermore, the pharmacological inhibition of class I HDACs sensitizes melanoma cells to apoptosis following exposure to DTIC and BMN-673. In addition, the inhibition of HDACs causes the sensitization of melanoma cells to DTIV and BMN-673 in melanoma xenografts in vivo. At the mRNA and protein level, the histone deacetylase inhibitor downregulated RAD51 and FANCD2. This study aims to demonstrate that combining an HDACi, alkylating agent and PARPi could potentially enhance the treatment of melanoma, which is commonly recognized as being among the most aggressive malignant tumors. The findings presented here point to a scenario in which HDACs, via enhancing the HR-dependent repair of DSBs created during the processing of DNA lesions, are essential nodes in the resistance of malignant melanoma cells to methylating agent-based therapies. Full article
(This article belongs to the Special Issue DNA Damage Induced by Anti-cancer Agents)
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11 pages, 1397 KiB  
Article
A Cell System-Assisted Strategy for Evaluating the Natural Antioxidant-Induced Double-Stranded DNA Break (DSB) Style
by Yuduki Someya, Sakine Kobayashi, Kazuya Toriumi, Shigeki Takeda, Noritaka Adachi and Aya Kurosawa
Genes 2023, 14(2), 420; https://doi.org/10.3390/genes14020420 - 06 Feb 2023
Cited by 1 | Viewed by 1704
Abstract
Natural antioxidants derived from plants exert various physiological effects, including antitumor effects. However, the molecular mechanisms of each natural antioxidant have not yet been fully elucidated. Identifying the targets of natural antioxidants with antitumor properties in vitro is costly and time-consuming, and the [...] Read more.
Natural antioxidants derived from plants exert various physiological effects, including antitumor effects. However, the molecular mechanisms of each natural antioxidant have not yet been fully elucidated. Identifying the targets of natural antioxidants with antitumor properties in vitro is costly and time-consuming, and the results thus obtained may not reliably reflect in vivo conditions. Therefore, to enhance understanding regarding the antitumor effects of natural antioxidants, we focused on DNA, one of the targets of anticancer drugs, and evaluated whether antioxidants, e.g., sulforaphane, resveratrol, quercetin, kaempferol, and genistein, which exert antitumor effects, induce DNA damage using gene-knockout cell lines derived from human Nalm-6 and HeLa cells pretreated with the DNA-dependent protein kinase inhibitor NU7026. Our results suggested that sulforaphane induces single-strand breaks or DNA strand crosslinks and that quercetin induces double-strand breaks. In contrast, resveratrol showed the ability to exert cytotoxic effects other than DNA damage. Our results also suggested that kaempferol and genistein induce DNA damage via unknown mechanisms. Taken together, the use of this evaluation system facilitates the analysis of the cytotoxic mechanisms of natural antioxidants. Full article
(This article belongs to the Special Issue DNA Damage Induced by Anti-cancer Agents)
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12 pages, 2550 KiB  
Article
Mitochondrial Factor C20orf7 Facilitates the EMT-Mediated Cancer Cell Migration and the Proliferation of Colon Cancer In Vitro and In Vivo
by Hou-Hsien Liu, Chia-Hwa Lee, Yi-Chen Hsieh, Jia-Huei Zheng, Yun-Ru Liu, Chia-Hsuan Chang and Er-Chieh Cho
Genes 2022, 13(11), 2111; https://doi.org/10.3390/genes13112111 - 14 Nov 2022
Viewed by 1389
Abstract
Colon cancer is a major malignant neoplasm with a low survival rate for late-stage patients. Therefore, the investigation of molecules regulating colon cancer progression and the discovery of novel therapeutic targets is critical. Mitochondria play a vital role in maintaining the homeostasis of [...] Read more.
Colon cancer is a major malignant neoplasm with a low survival rate for late-stage patients. Therefore, the investigation of molecules regulating colon cancer progression and the discovery of novel therapeutic targets is critical. Mitochondria play a vital role in maintaining the homeostasis of cells. Abnormal mitochondrial metabolism alterations and the induction of glycolysis can facilitate tumor growth; therefore, targeting mitochondrial molecules is suggested to be a promising strategy for cancer treatment. In this study, we investigated the role of this largely unknown mitochondrial factor, chromosome 20 open reading frame 7 (C20orf7), in colon cancer progression. Clustered regularly interspaced short palindromic repeats (CRISPR) technology was utilized for C20orf7 depletion, and functional assays were performed to examine the regulation of C20orf7 in colon cancer cells. We demonstrated that C20orf7 facilitates epithelial–mesenchymal transition (EMT)-mediated cell migration and promotes the proliferation of colon cancer. The anti-cancer drug 5-fluorouracil (5FU) was also applied, and C20orf7 was targeted with a combination of 5FU treatment, which could further enhance the anti-cancer effect in the colon cancer cell line and the xenograft mice model. In summary, this study demonstrated, for the first time, that C20orf7 plays a promotional role in cancer tumorigenesis and could be a promising therapeutic target in colon cancer treatment. Full article
(This article belongs to the Special Issue DNA Damage Induced by Anti-cancer Agents)
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Review

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10 pages, 421 KiB  
Review
Modulation of Skin Cancer by the Stimulator of Interferon Genes
by Max Oscherwitz, Victoria Jiminez, Hanna Terhaar and Nabiha Yusuf
Genes 2023, 14(9), 1794; https://doi.org/10.3390/genes14091794 - 13 Sep 2023
Viewed by 1035
Abstract
Morbidity and mortality from skin cancer continue to rise domestically and globally, and melanoma and non-melanoma skin cancers are a topic of interest in the dermatology and oncology communities. In this review, we summarize the stimulator of interferon genes (STING) pathway, its specific [...] Read more.
Morbidity and mortality from skin cancer continue to rise domestically and globally, and melanoma and non-melanoma skin cancers are a topic of interest in the dermatology and oncology communities. In this review, we summarize the stimulator of interferon genes (STING) pathway, its specific role in the pathogenesis of DNA damage and skin cancer, and STING-specific therapies that may fight both melanoma and non-melanoma skin (NMSC) cancers. Furthermore, we discuss specific portions of the STING pathway that may be used in addition to previously used therapies to provide a synergistic effect in future oncology treatments and discuss the limitations of current STING-based therapies. Full article
(This article belongs to the Special Issue DNA Damage Induced by Anti-cancer Agents)
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