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Nature Reviews. Cancer Mar 2022Tobacco products present a deadly combination of nicotine addiction and carcinogen exposure resulting in millions of cancer deaths per year worldwide. A plethora of... (Review)
Review
Tobacco products present a deadly combination of nicotine addiction and carcinogen exposure resulting in millions of cancer deaths per year worldwide. A plethora of smokeless tobacco products lead to unacceptable exposure to multiple carcinogens, including the tobacco-specific nitrosamine N'-nitrosonornicotine, a likely cause of the commonly occurring oral cavity cancers observed particularly in South-East Asian countries. Cigarettes continue to deliver a large number of carcinogens, including tobacco-specific nitrosamines, polycyclic aromatic hydrocarbons and volatile organic compounds. The multiple carcinogens in cigarette smoke are responsible for the complex mutations observed in critical cancer genes. The exposure of smokeless tobacco users and smokers to carcinogens and toxicants can now be monitored by urinary and DNA adduct biomarkers that may be able to identify those individuals at highest risk of cancer so that effective cancer prevention interventions can be initiated. Regulation of the levels of carcinogens, toxicants and nicotine in tobacco products and evidence-based tobacco control efforts are now recognized as established pathways to preventing tobacco related cancer.
Topics: Carcinogens; Cigarette Smoking; Humans; Mouth Neoplasms; Nicotiana; Tobacco, Smokeless
PubMed: 34980891
DOI: 10.1038/s41568-021-00423-4 -
Cells Oct 2023E-cigarette use has been reported to affect cell viability, induce DNA damage, and modulate an inflammatory response resulting in negative health consequences. Most... (Review)
Review
E-cigarette use has been reported to affect cell viability, induce DNA damage, and modulate an inflammatory response resulting in negative health consequences. Most studies focus on oral and lung disease associated with e-cigarette use. However, tissue damage can be found in the cardio-vascular system and even the bladder. While the levels of carcinogenic compounds found in e-cigarette aerosols are lower than those in conventional cigarette smoke, the toxicants generated by the heat of the vaping device may include probable human carcinogens. Furthermore, nicotine, although not a carcinogen, can be metabolized to nitrosamines. Nitrosamines are known carcinogens and have been shown to be present in the saliva of e-cig users, demonstrating the health risk of e-cigarette vaping. E-cig vape can induce DNA adducts, promoting oxidative stress and DNA damage and NF-kB-driven inflammation. Together, these processes increase the transcription of pro-inflammatory cytokines. This creates a microenvironment thought to play a key role in tumorigenesis, although it is too early to know the long-term effects of vaping. This review considers different aspects of e-cigarette-induced cellular changes, including the generation of reactive oxygen species, DNA damage, DNA repair, inflammation, and the possible tumorigenic effects.
Topics: Humans; Electronic Nicotine Delivery Systems; Vaping; Respiratory Aerosols and Droplets; Carcinogens; Epithelial Cells; Nitrosamines; Carcinogenesis; Inflammation; Tumor Microenvironment
PubMed: 37947630
DOI: 10.3390/cells12212552 -
Current Protocols Oct 2021Topoisomerases are enzymes that play essential roles in DNA replication, transcription, chromosome segregation, and recombination. All cells have two major forms of DNA...
Topoisomerases are enzymes that play essential roles in DNA replication, transcription, chromosome segregation, and recombination. All cells have two major forms of DNA topoisomerases: type I enzymes, which make single-stranded cuts in DNA, and type II enzymes, which cut and decatenate double-stranded DNA. DNA topoisomerases are important targets of approved and experimental anti-cancer agents. Provided in this article are protocols to assess activities of topoisomerases and their inhibitors. Included are an assay for topoisomerase I activity based on relaxation of supercoiled DNA; an assay for topoisomerase II based on the decatenation of double-stranded DNA; and approaches for enriching and quantifying DNA-protein covalent complexes formed as obligatory intermediates in the reactions of type I and II topoisomerases with DNA; and assays for measuring DNA cleavage in vitro. Topoisomerases are not the only proteins that form covalent adducts with DNA in living cells, and the approaches described here are likely to find use in characterizing other protein-DNA adducts and exploring their utility as targets for therapy. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Assay of topoisomerase I activity Basic Protocol 2: Assay of topoisomerase II activity Basic Protocol 3: In vivo determination of topoisomerase covalent complexes using the in vivo complex of enzyme (ICE) assay Support Protocol 1: Preparation of mouse tissue for determination of topoisomerase covalent complexes using the ICE assay Support Protocol 2: Using recombinant topoisomerase standard for absolute quantification of cellular TOP2CC Basic Protocol 4: Quantification of topoisomerase-DNA covalent complexes by RADAR/ELISA: The rapid approach to DNA adduct recovery (RADAR) combined with the enzyme-linked immunosorbent assay (ELISA) Basic Protocol 5: Analysis of protein-DNA covalent complexes by RADAR/Western Support Protocol 3: Adduct-Seq to characterize adducted DNA Support Protocol 4: Nuclear fractionation and RNase treatment to reduce sample complexity Basic Protocol 6: Determination of DNA cleavage by purified topoisomerase I Basic Protocol 7: Determination of inhibitor effects on DNA cleavage by topoisomerase II using a plasmid linearization assay Alternate Protocol: Gel electrophoresis determination of topoisomerase II cleavage.
Topics: Animals; DNA Cleavage; DNA Topoisomerases; DNA Topoisomerases, Type II; DNA, Superhelical; Mice; Plasmids
PubMed: 34606690
DOI: 10.1002/cpz1.250 -
International Journal of Molecular... Jun 2022Benzo[]pyrene (B[]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments.... (Review)
Review
Benzo[]pyrene (B[]P) is the main representative of polycyclic aromatic hydrocarbons (PAHs), and has been repeatedly found in the air, surface water, soil, and sediments. It is present in cigarette smoke as well as in food products, especially when smoked and grilled. Human exposure to B[]P is therefore common. Research shows growing evidence concerning toxic effects induced by this substance. This xenobiotic is metabolized by cytochrome P450 (CYP P450) to carcinogenic metabolite: 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo[]pyrene (BPDE), which creates DNA adducts, causing mutations and malignant transformations. Moreover, B[]P is epigenotoxic, neurotoxic, and teratogenic, and exhibits pro-oxidative potential and causes impairment of animals' fertility. CYP P450 is strongly involved in B[]P metabolism, and it is simultaneously expressed as a result of the association of B[]P with aromatic hydrocarbon receptor (AhR), playing an essential role in the cancerogenic potential of various xenobiotics. In turn, polymorphism of genes determines the sensitivity of the organism to B[]P. It was also observed that B[]P facilitates the multiplication of viruses, which may be an additional problem with the widespread COVID-19 pandemic. Based on publications mainly from 2017 to 2022, this paper presents the occurrence of B[]P in various environmental compartments and human surroundings, shows the exposure of humans to this substance, and describes the mechanisms of its toxicity.
Topics: Animals; Benzo(a)pyrene; COVID-19; Carcinogens; Cytochrome P-450 Enzyme System; DNA Adducts; Humans; Pandemics; Polycyclic Aromatic Hydrocarbons
PubMed: 35683027
DOI: 10.3390/ijms23116348 -
Clinical and Molecular Hepatology Oct 2020An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, cirrhosis, and lead to hepatocellular carcinoma (HCC). The aim of this review is to... (Review)
Review
An excessive alcohol intake may result in fatty liver, acute/chronic hepatitis, cirrhosis, and lead to hepatocellular carcinoma (HCC). The aim of this review is to clarify the present condition and the mechanisms of alcohol-related hepatocarcinogenesis and clinical risk factors for alcohol-related HCC. There are several possible mechanisms through which alcohol may induce hepatocarcinogenesis, including the mutagenic effects of acetaldehyde toxicity through the formation of protein and DNA adducts and the production of reactive oxygen species due to the excessive hepatic deposition of iron, changes to lipid peroxidation and metabolism, inflammation and an impaired immune response and modifications to DNA methylation. Furthermore, it has been reported that alcohol accelerates liver carcinogenesis through several signaling pathways including gut-liver axis. From a clinical perspective, it is well known that alcohol interacts with other factors, such as age, gender, viral hepatitis, obesity, and diabetes leading to an increased risk of HCC.
Topics: Carcinogenesis; Carcinoma, Hepatocellular; Ethanol; Humans; Liver Neoplasms; Risk Factors
PubMed: 33053943
DOI: 10.3350/cmh.2020.0203 -
Signal Transduction and Targeted Therapy Oct 2022Protein neddylation is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme, and an E3 ligase. In various types of human cancers, the...
Protein neddylation is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme, and an E3 ligase. In various types of human cancers, the neddylation pathway is abnormally activated. Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer. Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent, there are no small molecules available that selectively target UBE2F. Here, we report, for the first time, the discovery, via structure-based virtual screen and chemical optimization, of such a small molecule, designated as HA-9104. HA-9104 binds to UBE2F, reduces its protein levels, and consequently inhibits cullin-5 neddylation. Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5 (CRL5) activity, leading to accumulation of the CRL5 substrate, NOXA, to induce apoptosis. Moreover, HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest. Biologically, HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models. In summary, we discovered a small molecule, designated HA-9104, that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.
Topics: Apoptosis; Cell Line, Tumor; Cullin Proteins; Cyclopentanes; DNA Adducts; G2 Phase Cell Cycle Checkpoints; Humans; Lung Neoplasms; Pyrimidines; Ubiquitin-Conjugating Enzymes; Ubiquitin-Protein Ligases
PubMed: 36253371
DOI: 10.1038/s41392-022-01182-w -
International Journal of Molecular... May 2022The tobacco-specific -nitrosamines 4-(-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and '-nitrosonornicotine (NNN) always occur together and exclusively in tobacco... (Review)
Review
The tobacco-specific -nitrosamines 4-(-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK) and '-nitrosonornicotine (NNN) always occur together and exclusively in tobacco products or in environments contaminated by tobacco smoke. They have been classified as "carcinogenic to humans" by the International Agency for Research on Cancer. In 1998, we published a review of the biochemistry, biology and carcinogenicity of tobacco-specific nitrosamines. Over the past 20 years, considerable progress has been made in our understanding of the mechanisms of metabolism and DNA adduct formation by these two important carcinogens, along with progress on their carcinogenicity and mutagenicity. In this review, we aim to provide an update on the carcinogenicity and mechanisms of the metabolism and DNA interactions of NNK and NNN.
Topics: Carcinogens; DNA Adducts; Humans; Nitrosamines; Nicotiana; Tobacco Products
PubMed: 35563500
DOI: 10.3390/ijms23095109 -
Chemical Research in Toxicology Jul 2023Aldehydes are widespread in the environment, with multiple sources such as food and beverages, industrial effluents, cigarette smoke, and additives. The toxic effects of... (Review)
Review
Aldehydes are widespread in the environment, with multiple sources such as food and beverages, industrial effluents, cigarette smoke, and additives. The toxic effects of exposure to several aldehydes have been observed in numerous studies. At the molecular level, aldehydes damage DNA, cross-link DNA and proteins, lead to lipid peroxidation, and are associated with increased disease risk including cancer. People genetically predisposed to aldehyde sensitivity exhibit severe health outcomes. In various diseases such as Fanconi's anemia and Cockayne syndrome, loss of aldehyde-metabolizing pathways in conjunction with defects in DNA repair leads to widespread DNA damage. Importantly, aldehyde-associated mutagenicity is being explored in a growing number of studies, which could offer key insights into how they potentially contribute to tumorigenesis. Here, we review the genotoxic effects of various aldehydes, focusing particularly on the DNA adducts underlying the mutagenicity of environmentally derived aldehydes. We summarize the chemical structures of the aldehydes and their predominant DNA adducts, discuss various methodologies, and , commonly used in measuring aldehyde-associated mutagenesis, and highlight some recent studies looking at aldehyde-associated mutation signatures and spectra. We conclude the Review with a discussion on the challenges and future perspectives of investigating aldehyde-associated mutagenesis.
Topics: Humans; Aldehydes; DNA Adducts; DNA Damage; DNA Repair; Mutagens; DNA
PubMed: 37363863
DOI: 10.1021/acs.chemrestox.3c00045 -
Frontiers in Pharmacology 2021Auraptene is a bioactive monoterpene coumarin isolated from and that belong to the Rutaceae family. Auraptene can modulate intracellular signaling pathways that... (Review)
Review
Auraptene is a bioactive monoterpene coumarin isolated from and that belong to the Rutaceae family. Auraptene can modulate intracellular signaling pathways that control cell growth, inflammation and apoptosis and can exert pharmacological properties such as anti-bacterial, anti-fungal, antileishmania and anti-oxidant activity. Auraptene had inhibitory and chemo-preventive effects on the proliferation, tumorigenesis and growth of several cancer cell lines through increase in the activity of glutathione S-transferase, formation of DNA adducts and reduction of the number of aberrant crypt foci. Auraptene exhibits anticancer effects via targeting different cell signaling pathways such as cytokines, genes modulating cellular proliferation, growth factors, transcription factors and apoptosis. The present review is a detailed survey of scientific researches on the cytotoxicity and anticancer activity of Auraptene on cancer cells and tumor bearing animals.
PubMed: 34239445
DOI: 10.3389/fphar.2021.698352 -
Mutation Research. Reviews in Mutation... 2022The allure of tobacco smoking is linked to the instant gratification provided by inhaled nicotine. Unfortunately, tobacco curing and burning generates many mutagens... (Review)
Review
The allure of tobacco smoking is linked to the instant gratification provided by inhaled nicotine. Unfortunately, tobacco curing and burning generates many mutagens including more than 70 carcinogens. There are two types of mutagens and carcinogens in tobacco smoke (TS): direct DNA damaging carcinogens and procarcinogens, which require metabolic activation to become DNA damaging. Recent studies provide three new insights on TS-induced DNA damage. First, two major types of TS DNA damage are induced by direct carcinogen aldehydes, cyclic-1,N-hydroxy-deoxyguanosine (γ-OH-PdG) and α-methyl-1, N-γ-OH-PdG, rather than by the procarcinogens, polycyclic aromatic hydrocarbons and aromatic amines. Second, TS reduces DNA repair proteins and activity levels. TS aldehydes also prevent procarcinogen activation. Based on these findings, we propose that aldehydes are major sources of TS induce DNA damage and a driving force for carcinogenesis. E-cigarettes (E-cigs) are designed to deliver nicotine in an aerosol state, without burning tobacco. E-cigarette aerosols (ECAs) contain nicotine, propylene glycol and vegetable glycerin. ECAs induce O-methyl-deoxyguanosines (O-medG) and cyclic γ-hydroxy-1,N--propano-dG (γ-OH-PdG) in mouse lung, heart and bladder tissues and causes a reduction of DNA repair proteins and activity in lungs. Nicotine and nicotine-derived nitrosamine ketone (NNK) induce the same types of DNA adducts and cause DNA repair inhibition in human cells. After long-term exposure, ECAs induce lung adenocarcinoma and bladder urothelial hyperplasia in mice. We propose that E-cig nicotine can be nitrosated in mouse and human cells becoming nitrosamines, thereby causing two carcinogenic effects, induction of DNA damage and inhibition of DNA repair, and that ECA is carcinogenic in mice. Thus, this article reviews the newest literature on DNA adducts and DNA repair inhibition induced by nicotine and ECAs in mice and cultured human cells, and provides insights into ECA carcinogenicity in mice.
Topics: Aerosols; Aldehydes; Animals; Carcinogenesis; Carcinogens; DNA Adducts; DNA Damage; DNA Repair; Electronic Nicotine Delivery Systems; Humans; Mice; Mutagens; Nicotine; Smoke; Nicotiana; Tobacco Smoke Pollution
PubMed: 35690412
DOI: 10.1016/j.mrrev.2021.108409