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Special Issue "Chemically-Induced DNA Damage, Mutagenesis, and Cancer"

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

Deadline for manuscript submissions: closed (15 October 2017)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Guest Editor
Prof. Dr. Ashis Basu

Department of Chemistry, University of Connecticut, Storrs, CT 06269, USA
Website | E-Mail
Interests: carcinogen-nucleic acid interactions; DNA damage; DNA repair; cross-links in DNA; mechanism of mutation and cancer; chemistry and biology of natural products with antitumor properties
Guest Editor
Prof. Dr. Takehiko Nohmi

Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan
Website | E-Mail
Interests: Genotoxicity; DNA damage; mutation; translesion synthesis; DNA repair; DNA polymerase; risk assessment; chemical carcinogens

Special Issue Information

Dear Colleagues,

A large number of chemicals have been associated with the etiology of human cancers. DNA damage induced by a chemical in a cell is an important first step in the process of chemical carcinogenesis. Various DNA repair mechanisms have evolved to take care of the DNA damages, but they cannot repair every single one, especially when the damages are induced at a high frequency. Replication of damaged DNA increases the rate of polymerase errors, resulting in gene mutations, which may lead to the synthesis of altered proteins. Mutations in an oncogene, a tumor-suppressor gene, or a gene that controls the cell cycle can give rise to a clonal cell population with a distinct advantage in proliferation. Many such events, occurring over a long period of time and taking place within the context of chronic exposure to chemical mutagens, can lead to the induction of human cancer. This is exemplified in the long-term use of tobacco being responsible for an increased risk of lung cancer. The aim of this Special Issue is to provide a broad overview on the topic of the “consequence of DNA damage” in the context of human cancer with their challenges and highlights. We ask the experts in the field to contribute their latest research, perspective, or reviews on this fascinating and rapidly progressing topic.

Prof. Dr. Ashis Basu
Guest Editor

Manuscript Submission Information

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Keywords

  • DNA damage
  • Carcinogen-DNA adduct
  • Genotoxicity
  • DNA repair
  • Mutation
  • Mutagenesis
  • Carcinogenesis
  • Trans-lesion synthesis
  • DNA polymerase

Published Papers (16 papers)

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Editorial

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Open AccessEditorial Chemically-Induced DNA Damage, Mutagenesis, and Cancer
Int. J. Mol. Sci. 2018, 19(6), 1767; https://doi.org/10.3390/ijms19061767
Received: 23 May 2018 / Revised: 11 June 2018 / Accepted: 12 June 2018 / Published: 14 June 2018
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Research

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Open AccessArticle High NOTCH1 mRNA Expression Is Associated with Better Survival in HNSCC
Int. J. Mol. Sci. 2018, 19(3), 830; https://doi.org/10.3390/ijms19030830
Received: 25 February 2018 / Revised: 4 March 2018 / Accepted: 6 March 2018 / Published: 13 March 2018
Cited by 1 | PDF Full-text (1520 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The clinical impact of the expression of NOTCH1 signaling components in squamous cell carcinoma of the pharynx and larynx has only been evaluated in subgroups. The aim of this study was therefore to evaluate NOTCH1 expression in head and neck squamous cell cancer [...] Read more.
The clinical impact of the expression of NOTCH1 signaling components in squamous cell carcinoma of the pharynx and larynx has only been evaluated in subgroups. The aim of this study was therefore to evaluate NOTCH1 expression in head and neck squamous cell cancer (HNSCC) patient tissue and cell lines. We analyzed tissue from 195 HNSCCs and tissue from 30 normal patients for mRNA expression of NOTCH1, NOTCH3, HES1, HEY1, and JAG1 using quantitative real-time PCR. Association of expression results and clinical orpathological factors was examined with multivariate Cox regression. NOTCH1 expression was determined in three Human Papilloma Virus (HPV)-positive and nine HPV-negative HNSCC cell lines. High expression of NOTCH1 was associated with better overall survival (p = 0.013) and disease-free survival (p = 0.040). Multivariate Cox regression confirmed the significant influence of NOTCH1 expression on overall survival (p = 0.033) and disease-free survival (p = 0.029). A significant correlation was found between p16 staining and NOTCH1 mRNA expression (correlation coefficient 0.28; p = 0.01). NOTCH1 was expressed at higher levels in HPV-positive HNSCC cell lines compared with HPV-negative cell lines, which was not statistically significant (p = 0.068). We conclude that NOTCH1 expression is associated with overall survival, and that inhibition of NOTCH1 therefore seems less promising. Full article
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Open AccessArticle A Case-Control Study of the Genetic Variability in Reactive Oxygen Species—Metabolizing Enzymes in Melanoma Risk
Int. J. Mol. Sci. 2018, 19(1), 242; https://doi.org/10.3390/ijms19010242
Received: 18 December 2017 / Revised: 9 January 2018 / Accepted: 12 January 2018 / Published: 14 January 2018
Cited by 3 | PDF Full-text (1048 KB) | HTML Full-text | XML Full-text
Abstract
Recent studies have shown that ultraviolet (UV)-induced chemiexcitation of melanin fragments leads to DNA damage; and chemiexcitation of melanin fragments requires reactive oxygen species (ROS), as ROS excite an electron in the melanin fragments. In addition, ROS also cause DNA damages on their [...] Read more.
Recent studies have shown that ultraviolet (UV)-induced chemiexcitation of melanin fragments leads to DNA damage; and chemiexcitation of melanin fragments requires reactive oxygen species (ROS), as ROS excite an electron in the melanin fragments. In addition, ROS also cause DNA damages on their own. We hypothesized that ROS producing and metabolizing enzymes were major contributors in UV-driven melanomas. In this case-control study of 349 participants, we genotyped 23 prioritized single nucleotide polymorphisms (SNPs) in nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4 (NOX1 and NOX4, respectively), CYBA, RAC1, superoxide dismutases (SOD1, SOD2, and SOD3) and catalase (CAT), and analyzed their associated melanoma risk. Five SNPs, namely rs1049255 (CYBA), rs4673 (CYBA), rs10951982 (RAC1), rs8031 (SOD2), and rs2536512 (SOD3), exhibited significant genotypic frequency differences between melanoma cases and healthy controls. In simple logistic regression, RAC1 rs10951982 (odds ratio (OR) 8.98, 95% confidence interval (CI): 5.08 to 16.44; p < 0.001) reached universal significance (p = 0.002) and the minor alleles were associated with increased risk of melanoma. In contrast, minor alleles in SOD2 rs8031 (OR 0.16, 95% CI: 0.06 to 0.39; p < 0.001) and SOD3 rs2536512 (OR 0.08, 95% CI: 0.01 to 0.31; p = 0.001) were associated with reduced risk of melanoma. In multivariate logistic regression, RAC1 rs10951982 (OR 6.15, 95% CI: 2.98 to 13.41; p < 0.001) remained significantly associated with increased risk of melanoma. Our results highlighted the importance of RAC1, SOD2, and SOD3 variants in the risk of melanoma. Full article
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Open AccessArticle Enhanced Susceptibility of Ogg1 Mutant Mice to Multiorgan Carcinogenesis
Int. J. Mol. Sci. 2017, 18(8), 1801; https://doi.org/10.3390/ijms18081801
Received: 18 July 2017 / Revised: 13 August 2017 / Accepted: 15 August 2017 / Published: 18 August 2017
Cited by 4 | PDF Full-text (2620 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The role of deficiency of oxoguanine glycosylase 1 (Ogg1) Mmh homolog, a repair enzyme of the 8-hydroxy-2’-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J [...] Read more.
The role of deficiency of oxoguanine glycosylase 1 (Ogg1) Mmh homolog, a repair enzyme of the 8-hydroxy-2’-deoxyguanosine (8-OHdG) residue in DNA, was investigated using the multiorgan carcinogenesis bioassay in mice. A total of 80 male and female six-week-old mice of C57BL/6J background carrying a mutant Mmh allele of the Mmh/Ogg1 gene (Ogg1/) and wild type (Ogg1+/+) mice were administered N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), N-bis (2-hydroxypropyl) nitrosamine (DHPN) and 1,2-dimethylhydrazine dihydrochloride (DMH) (DMBDD) to induce carcinogenesis in multiple organs, and observed up to 34 weeks. Significant increase of lung adenocarcinomas incidence was observed in DMBDD-treated Ogg1/ male mice, but not in DMBDD-administered Ogg1+/+ animals. Furthermore, incidences of lung adenomas were significantly elevated in both Ogg1/ males and females as compared with respective Ogg1/ control and DMBDD-treated Ogg1+/+ groups. Incidence of total liver tumors (hepatocellular adenomas, hemangiomas and hemangiosarcomas) was significantly higher in the DMBDD-administered Ogg1/ males and females. In addition, in DMBDD-treated male Ogg1/ mice, incidences of colon adenomas and total colon tumors showed a trend and a significant increase, respectively, along with significant rise in incidence of simple hyperplasia of the urinary bladder, and a trend to increase for renal tubules hyperplasia in the kidney. Furthermore, incidence of squamous cell hyperplasia in the forestomach of DMBDD-treated Ogg1/ male mice was significantly higher than that of Ogg1+/+ males. Incidence of small intestine adenomas in DMBDD Ogg1/ groups showed a trend for increase, as compared to the wild type mice. The current results demonstrated increased susceptibility of Ogg1 mutant mice to the multiorgan carcinogenesis induced by DMBDD. The present bioassay could become a useful tool to examine the influence of various targets on mouse carcinogenesis. Full article
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Open AccessArticle The Effect of VPA on Increasing Radiosensitivity in Osteosarcoma Cells and Primary-Culture Cells from Chemical Carcinogen-Induced Breast Cancer in Rats
Int. J. Mol. Sci. 2017, 18(5), 1027; https://doi.org/10.3390/ijms18051027
Received: 30 March 2017 / Revised: 30 April 2017 / Accepted: 5 May 2017 / Published: 10 May 2017
Cited by 5 | PDF Full-text (3081 KB) | HTML Full-text | XML Full-text
Abstract
This study explored whether valproic acid (VPA, a histone deacetylase inhibitor) could radiosensitize osteosarcoma and primary-culture tumor cells, and determined the mechanism of VPA-induced radiosensitization. The working system included osteosarcoma cells (U2OS) and primary-culture cells from chemical carcinogen (DMBA)-induced breast cancer in rats; [...] Read more.
This study explored whether valproic acid (VPA, a histone deacetylase inhibitor) could radiosensitize osteosarcoma and primary-culture tumor cells, and determined the mechanism of VPA-induced radiosensitization. The working system included osteosarcoma cells (U2OS) and primary-culture cells from chemical carcinogen (DMBA)-induced breast cancer in rats; and clonogenic survival, immunofluorescence, fluorescent in situ hybridization (FISH) for chromosome aberrations, and comet assays were used in this study. It was found that VPA at the safe or critical safe concentration of 0.5 or 1.0 mM VPA could result in the accumulation of more ionizing radiation (IR)-induced DNA double strand breaks, and increase the cell radiosensitivity. VPA-induced radiosensitivity was associated with the inhibition of DNA repair activity in the working systems. In addition, the chromosome aberrations including chromosome breaks, chromatid breaks, and radial structures significantly increased after the combination treatment of VPA and IR. Importantly, the results obtained by primary-culture cells from the tissue of chemical carcinogen-induced breast cancer in rats further confirmed our findings. The data in this study demonstrated that VPA at a safe dose was a radiosensitizer for osteosarcoma and primary-culture tumor cells through suppressing DNA-double strand breaks repair function. Full article
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Open AccessArticle Magnetic Hyperthermia and Oxidative Damage to DNA of Human Hepatocarcinoma Cells
Int. J. Mol. Sci. 2017, 18(5), 939; https://doi.org/10.3390/ijms18050939
Received: 1 March 2017 / Revised: 13 April 2017 / Accepted: 23 April 2017 / Published: 29 April 2017
Cited by 3 | PDF Full-text (1755 KB) | HTML Full-text | XML Full-text
Abstract
Nanotechnology is addressing major urgent needs for cancer treatment. We conducted a study to compare the frequency of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) adducts, biomarkers of oxidative stress and/or lipid peroxidation, on human hepatocarcinoma HepG2 cells exposed to [...] Read more.
Nanotechnology is addressing major urgent needs for cancer treatment. We conducted a study to compare the frequency of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) adducts, biomarkers of oxidative stress and/or lipid peroxidation, on human hepatocarcinoma HepG2 cells exposed to increasing levels of Fe3O4-nanoparticles (NPs) versus untreated cells at different lengths of incubations, and in the presence of increasing exposures to an alternating magnetic field (AMF) of 186 kHz using 32P-postlabeling. The levels of oxidative damage tended to increase significantly after ≥24 h of incubations compared to controls. The oxidative DNA damage tended to reach a steady-state after treatment with 60 μg/mL of Fe3O4-NPs. Significant dose–response relationships were observed. A greater adduct production was observed after magnetic hyperthermia, with the highest amounts of oxidative lesions after 40 min exposure to AMF. The effects of magnetic hyperthermia were significantly increased with exposure and incubation times. Most important, the levels of oxidative lesions in AMF exposed NP treated cells were up to 20-fold greater relative to those observed in nonexposed NP treated cells. Generation of oxidative lesions may be a mechanism by which magnetic hyperthermia induces cancer cell death. Full article
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Open AccessArticle CoQ10 Deficiency May Indicate Mitochondrial Dysfunction in Cr(VI) Toxicity
Int. J. Mol. Sci. 2017, 18(4), 816; https://doi.org/10.3390/ijms18040816
Received: 11 February 2017 / Revised: 3 April 2017 / Accepted: 7 April 2017 / Published: 24 April 2017
Cited by 5 | PDF Full-text (2427 KB) | HTML Full-text | XML Full-text
Abstract
To investigate the toxic mechanism of hexavalent chromium Cr(VI) and search for an antidote for Cr(VI)-induced cytotoxicity, a study of mitochondrial dysfunction induced by Cr(VI) and cell survival by recovering mitochondrial function was performed. In the present study, we found that the gene [...] Read more.
To investigate the toxic mechanism of hexavalent chromium Cr(VI) and search for an antidote for Cr(VI)-induced cytotoxicity, a study of mitochondrial dysfunction induced by Cr(VI) and cell survival by recovering mitochondrial function was performed. In the present study, we found that the gene expression of electron transfer flavoprotein dehydrogenase (ETFDH) was strongly downregulated by Cr(VI) exposure. The levels of coenzyme 10 (CoQ10) and mitochondrial biogenesis presented by mitochondrial mass and mitochondrial DNA copy number were also significantly reduced after Cr(VI) exposure. The subsequent, Cr(VI)-induced mitochondrial damage and apoptosis were characterized by reactive oxygen species (ROS) accumulation, caspase-3 and caspase-9 activation, decreased superoxide dismutase (SOD) and ATP production, increased methane dicarboxylic aldehyde (MDA) content, mitochondrial membrane depolarization and mitochondrial permeability transition pore (MPTP) opening, increased Ca2+ levels, Cyt c release, decreased Bcl-2 expression, and significantly elevated Bax expression. The Cr(VI)-induced deleterious changes were attenuated by pretreatment with CoQ10 in L-02 hepatocytes. These data suggest that Cr(VI) induces CoQ10 deficiency in L-02 hepatocytes, indicating that this deficiency may be a biomarker of mitochondrial dysfunction in Cr(VI) poisoning and that exogenous administration of CoQ10 may restore mitochondrial function and protect the liver from Cr(VI) exposure. Full article
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Open AccessArticle Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice
Int. J. Mol. Sci. 2017, 18(3), 465; https://doi.org/10.3390/ijms18030465
Received: 13 December 2016 / Revised: 8 February 2017 / Accepted: 13 February 2017 / Published: 24 February 2017
Cited by 5 | PDF Full-text (4752 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible [...] Read more.
Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future. Full article
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Review

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Open AccessReview DNA Damage, Mutagenesis and Cancer
Int. J. Mol. Sci. 2018, 19(4), 970; https://doi.org/10.3390/ijms19040970
Received: 29 January 2018 / Revised: 16 March 2018 / Accepted: 20 March 2018 / Published: 23 March 2018
Cited by 11 | PDF Full-text (1523 KB) | HTML Full-text | XML Full-text
Abstract
A large number of chemicals and several physical agents, such as UV light and γ-radiation, have been associated with the etiology of human cancer. Generation of DNA damage (also known as DNA adducts or lesions) induced by these agents is an important first [...] Read more.
A large number of chemicals and several physical agents, such as UV light and γ-radiation, have been associated with the etiology of human cancer. Generation of DNA damage (also known as DNA adducts or lesions) induced by these agents is an important first step in the process of carcinogenesis. Evolutionary processes gave rise to DNA repair tools that are efficient in repairing damaged DNA; yet replication of damaged DNA may take place prior to repair, particularly when they are induced at a high frequency. Damaged DNA replication may lead to gene mutations, which in turn may give rise to altered proteins. Mutations in an oncogene, a tumor-suppressor gene, or a gene that controls the cell cycle can generate a clonal cell population with a distinct advantage in proliferation. Many such events, broadly divided into the stages of initiation, promotion, and progression, which may occur over a long period of time and transpire in the context of chronic exposure to carcinogens, can lead to the induction of human cancer. This is exemplified in the long-term use of tobacco being responsible for an increased risk of lung cancer. This mini-review attempts to summarize this wide area that centers on DNA damage as it relates to the development of human cancer. Full article
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Open AccessReview Every OGT Is Illuminated … by Fluorescent and Synchrotron Lights
Int. J. Mol. Sci. 2017, 18(12), 2613; https://doi.org/10.3390/ijms18122613
Received: 15 November 2017 / Revised: 28 November 2017 / Accepted: 30 November 2017 / Published: 5 December 2017
Cited by 3 | PDF Full-text (3379 KB) | HTML Full-text | XML Full-text
Abstract
O6-DNA-alkyl-guanine-DNA-alkyl-transferases (OGTs) are evolutionarily conserved, unique proteins that repair alkylation lesions in DNA in a single step reaction. Alkylating agents are environmental pollutants as well as by-products of cellular reactions, but are also very effective chemotherapeutic drugs. OGTs are major players [...] Read more.
O6-DNA-alkyl-guanine-DNA-alkyl-transferases (OGTs) are evolutionarily conserved, unique proteins that repair alkylation lesions in DNA in a single step reaction. Alkylating agents are environmental pollutants as well as by-products of cellular reactions, but are also very effective chemotherapeutic drugs. OGTs are major players in counteracting the effects of such agents, thus their action in turn affects genome integrity, survival of organisms under challenging conditions and response to chemotherapy. Numerous studies on OGTs from eukaryotes, bacteria and archaea have been reported, highlighting amazing features that make OGTs unique proteins in their reaction mechanism as well as post-reaction fate. This review reports recent functional and structural data on two prokaryotic OGTs, from the pathogenic bacterium Mycobacterium tuberculosis and the hyperthermophilic archaeon Sulfolobus solfataricus, respectively. These studies provided insight in the role of OGTs in the biology of these microorganisms, but also important hints useful to understand the general properties of this class of proteins. Full article
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Open AccessReview The Role of Resveratrol in Cancer Therapy
Int. J. Mol. Sci. 2017, 18(12), 2589; https://doi.org/10.3390/ijms18122589
Received: 15 November 2017 / Revised: 27 November 2017 / Accepted: 29 November 2017 / Published: 1 December 2017
Cited by 32 | PDF Full-text (679 KB) | HTML Full-text | XML Full-text
Abstract
Abstract: Natural product compounds have recently attracted significant attention from the scientific community for their potent effects against inflammation-driven diseases, including cancer. A significant amount of research, including preclinical, clinical, and epidemiological studies, has indicated that dietary consumption of polyphenols, found at [...] Read more.
Abstract: Natural product compounds have recently attracted significant attention from the scientific community for their potent effects against inflammation-driven diseases, including cancer. A significant amount of research, including preclinical, clinical, and epidemiological studies, has indicated that dietary consumption of polyphenols, found at high levels in cereals, pulses, vegetables, and fruits, may prevent the evolution of an array of diseases, including cancer. Cancer development is a carefully orchestrated progression where normal cells acquires mutations in their genetic makeup, which cause the cells to continuously grow, colonize, and metastasize to other organs such as the liver, lungs, colon, and brain. Compounds that modulate these oncogenic processes can be considered as potential anti-cancer agents that may ultimately make it to clinical application. Resveratrol, a natural stilbene and a non-flavonoid polyphenol, is a phytoestrogen that possesses anti-oxidant, anti-inflammatory, cardioprotective, and anti-cancer properties. It has been reported that resveratrol can reverse multidrug resistance in cancer cells, and, when used in combination with clinically used drugs, it can sensitize cancer cells to standard chemotherapeutic agents. Several novel analogs of resveratrol have been developed with improved anti-cancer activity, bioavailability, and pharmacokinetic profile. The current focus of this review is resveratrol’s in vivo and in vitro effects in a variety of cancers, and intracellular molecular targets modulated by this polyphenol. This is also accompanied by a comprehensive update of the various clinical trials that have demonstrated it to be a promising therapeutic and chemopreventive agent. Full article
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Open AccessReview Dynamic Reorganization of the Cytoskeleton during Apoptosis: The Two Coffins Hypothesis
Int. J. Mol. Sci. 2017, 18(11), 2393; https://doi.org/10.3390/ijms18112393
Received: 14 October 2017 / Revised: 9 November 2017 / Accepted: 9 November 2017 / Published: 11 November 2017
Cited by 7 | PDF Full-text (1711 KB) | HTML Full-text | XML Full-text
Abstract
During apoptosis, cells undergo characteristic morphological changes in which the cytoskeleton plays an active role. The cytoskeleton rearrangements have been mainly attributed to actinomyosin ring contraction, while microtubule and intermediate filaments are depolymerized at early stages of apoptosis. However, recent results have shown [...] Read more.
During apoptosis, cells undergo characteristic morphological changes in which the cytoskeleton plays an active role. The cytoskeleton rearrangements have been mainly attributed to actinomyosin ring contraction, while microtubule and intermediate filaments are depolymerized at early stages of apoptosis. However, recent results have shown that microtubules are reorganized during the execution phase of apoptosis forming an apoptotic microtubule network (AMN). Evidence suggests that AMN is required to maintain plasma membrane integrity and cell morphology during the execution phase of apoptosis. The new “two coffins” hypothesis proposes that both AMN and apoptotic cells can adopt two morphological patterns, round or irregular, which result from different cytoskeleton kinetic reorganization during the execution phase of apoptosis induced by genotoxic agents. In addition, round and irregular-shaped apoptosis showed different biological properties with respect to AMN maintenance, plasma membrane integrity and phagocyte responses. These findings suggest that knowing the type of apoptosis may be important to predict how fast apoptotic cells undergo secondary necrosis and the subsequent immune response. From a pathological point of view, round-shaped apoptosis can be seen as a physiological and controlled type of apoptosis, while irregular-shaped apoptosis can be considered as a pathological type of cell death closer to necrosis. Full article
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Open AccessReview DNA Damage Tolerance by Eukaryotic DNA Polymerase and Primase PrimPol
Int. J. Mol. Sci. 2017, 18(7), 1584; https://doi.org/10.3390/ijms18071584
Received: 26 June 2017 / Revised: 14 July 2017 / Accepted: 16 July 2017 / Published: 21 July 2017
Cited by 4 | PDF Full-text (1254 KB) | HTML Full-text | XML Full-text
Abstract
PrimPol is a human deoxyribonucleic acid (DNA) polymerase that also possesses primase activity and is involved in DNA damage tolerance, the prevention of genome instability and mitochondrial DNA maintenance. In this review, we focus on recent advances in biochemical and crystallographic studies of [...] Read more.
PrimPol is a human deoxyribonucleic acid (DNA) polymerase that also possesses primase activity and is involved in DNA damage tolerance, the prevention of genome instability and mitochondrial DNA maintenance. In this review, we focus on recent advances in biochemical and crystallographic studies of PrimPol, as well as in identification of new protein-protein interaction partners. Furthermore, we discuss the possible functions of PrimPol in both the nucleus and the mitochondria. Full article
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Open AccessReview Exposure to Engineered Nanomaterials: Impact on DNA Repair Pathways
Int. J. Mol. Sci. 2017, 18(7), 1515; https://doi.org/10.3390/ijms18071515
Received: 13 June 2017 / Revised: 30 June 2017 / Accepted: 4 July 2017 / Published: 13 July 2017
Cited by 1 | PDF Full-text (507 KB) | HTML Full-text | XML Full-text
Abstract
Some engineered nanomaterials (ENMs) may have the potential to cause damage to the genetic material in living systems. The mechanistic machinery functioning at the cellular/molecular level, in the form of DNA repair processes, has evolved to help circumvent DNA damage caused by exposure [...] Read more.
Some engineered nanomaterials (ENMs) may have the potential to cause damage to the genetic material in living systems. The mechanistic machinery functioning at the cellular/molecular level, in the form of DNA repair processes, has evolved to help circumvent DNA damage caused by exposure to a variety of foreign substances. Recent studies have contributed to our understanding of the various DNA damage repair pathways involved in the processing of DNA damage. However, the vast array of ENMs may present a relatively new challenge to the integrity of the human genome; therefore, the potential hazard posed by some ENMs necessitates the evaluation and understanding of ENM-induced DNA damage repair pathways. This review focuses on recent studies highlighting the differential regulation of DNA repair pathways, in response to a variety of ENMs, and discusses the various factors that dictate aberrant repair processes, including intracellular signalling, spatial interactions and ENM-specific responses. Full article
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Open AccessReview Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome
Int. J. Mol. Sci. 2017, 18(5), 928; https://doi.org/10.3390/ijms18050928
Received: 20 March 2017 / Revised: 18 April 2017 / Accepted: 25 April 2017 / Published: 28 April 2017
Cited by 15 | PDF Full-text (1143 KB) | HTML Full-text | XML Full-text
Abstract
Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an [...] Read more.
Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or eliminate highly injured cells from the proliferating population. The wild-type p53 tumor suppressor and its downstream effector p21WAF1 (p21) are key regulators of these responses. Although extensively studied for its ability to control cell cycle progression, p21 has emerged as a multifunctional protein capable of downregulating p53, suppressing apoptosis, and orchestrating prolonged growth arrest through stress-induced premature senescence. Studies with solid tumors and solid tumor-derived cell lines have revealed that such growth-arrested cancer cells remain viable, secrete growth-promoting factors, and can give rise to progeny with stem-cell-like properties. This article provides an overview of the mechanisms by which p53 signaling suppresses apoptosis following genotoxic stress, facilitating repair of genomic injury under physiological conditions but having the potential to promote tumor regrowth in response to cancer chemotherapy. Full article
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Other

Open AccessPerspective The Future of DNA Adductomic Analysis
Int. J. Mol. Sci. 2017, 18(9), 1870; https://doi.org/10.3390/ijms18091870
Received: 13 July 2017 / Revised: 19 August 2017 / Accepted: 22 August 2017 / Published: 29 August 2017
Cited by 10 | PDF Full-text (1163 KB) | HTML Full-text | XML Full-text
Abstract
Covalent modification of DNA, resulting in the formation of DNA adducts, plays a central role in chemical carcinogenesis. Investigating these modifications is of fundamental importance in assessing the mutagenicity potential of specific exposures and understanding their mechanisms of action. Methods for assessing the [...] Read more.
Covalent modification of DNA, resulting in the formation of DNA adducts, plays a central role in chemical carcinogenesis. Investigating these modifications is of fundamental importance in assessing the mutagenicity potential of specific exposures and understanding their mechanisms of action. Methods for assessing the covalent modification of DNA, which is one of the initiating steps for mutagenesis, include immunohistochemistry, 32P-postlabeling, and mass spectrometry-based techniques. However, a tool to comprehensively characterize the covalent modification of DNA, screening for all DNA adducts and gaining information on their chemical structures, was lacking until the recent development of “DNA adductomics”. Advances in the field of mass spectrometry have allowed for the development of this methodology. In this perspective, we discuss the current state of the field, highlight the latest developments, and consider the path forward for DNA adductomics to become a standard method to investigate covalent modification of DNA. We specifically advocate for the need to take full advantage of this new era of mass spectrometry to acquire the highest quality and most reliable data possible, as we believe this is the only way for DNA adductomics to gain its place next to the other “-omics” methodologies as a powerful bioanalytical tool. Full article
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Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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