RESUMO
Tobacco use is a major cause of preventable morbidity and mortality globally. Tobacco products, including smokeless tobacco (ST), generally contain tobacco-specific N-nitrosamines (TSNAs), such as N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-butanone (NNK), which are potent carcinogens that cause mutations in critical genes in human DNA. This review covers the series of biochemical and chemical transformations, related to TSNAs, leading from tobacco cultivation to cancer initiation. A key aim of this review is to provide a greater understanding of TSNAs: their precursors, the microbial and chemical mechanisms that contribute to their formation in ST, their mutagenicity leading to cancer due to ST use, and potential means of lowering TSNA levels in tobacco products. TSNAs are not present in harvested tobacco but can form due to nitrosating agents reacting with tobacco alkaloids present in tobacco during certain types of curing. TSNAs can also form during or following ST production when certain microorganisms perform nitrate metabolism, with dissimilatory nitrate reductases converting nitrate to nitrite that is then released into tobacco and reacts chemically with tobacco alkaloids. When ST usage occurs, TSNAs are absorbed and metabolized to reactive compounds that form DNA adducts leading to mutations in critical target genes, including the RAS oncogenes and the p53 tumor suppressor gene. DNA repair mechanisms remove most adducts induced by carcinogens, thus preventing many but not all mutations. Lastly, because TSNAs and other agents cause cancer, previously documented strategies for lowering their levels in ST products are discussed, including using tobacco with lower nornicotine levels, pasteurization and other means of eliminating microorganisms, omitting fermentation and fire-curing, refrigerating ST products, and including nitrite scavenging chemicals as ST ingredients.
Assuntos
Neoplasias , Nitrosaminas , Tabaco sem Fumaça , Humanos , Carcinógenos/toxicidade , Mutagênicos , Neoplasias/induzido quimicamente , Nitratos , Nitritos , Nitrosaminas/toxicidade , Nitrosaminas/química , Nitrosaminas/metabolismo , Tabaco sem Fumaça/toxicidadeRESUMO
Smokeless tobacco (SLT) use is a significant cause of lip and oral cavity cancers. Globally, oral cancer prevalence is strongly linked to the types of tobacco products used, their chemical composition, and their pattern of use. Except snus, all SLT products sold in different World Health Organization regions are strongly associated with oral cancer incidence. Shammah showed the highest association OR with 95% confidence intervals (CI; OR, 38.74; 95% CI, 19.50-76.96), followed by oral snuff (OR, 11.80; 95% CI, 8.45-16.49), gutkha (OR, 8.67; 95% CI, 3.59-20.93), tobacco with betel quid (OR, 7.74; 95% CI, 5.38-11.13), toombak (OR, 4.72; 95% CI, 2.88-7.73), and unspecified chewing tobacco (OR, 4.72; 95% CI, 3.13-7.11). Most SLT products containing high levels of carcinogenic tobacco-specific nitrosamines (TSNA) exhibit a high risk of oral cancer. There is an urgent need to frame and implement international policies for oral cancer prevention through legal control of the TSNA levels in all SLT product types. PREVENTION RELEVANCE: Most smokeless tobacco products sold worldwide, mainly shammah, toombak, gutkha, betel quid with tobacco, and dry snuff, are associated with a high risk of oral cancer. A high concentration of tobacco-specific nitrosamines in smokeless tobacco products is the major causative factor for oral cancer development.
Assuntos
Neoplasias Bucais , Uso de Tabaco , Tabaco sem Fumaça , Humanos , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/etiologia , Nitrosaminas , Medição de Risco , Uso de Tabaco/efeitos adversos , Uso de Tabaco/epidemiologia , Tabaco sem Fumaça/análise , Tabaco sem Fumaça/toxicidade , Literatura de Revisão como Assunto , Metanálise como AssuntoRESUMO
Adolescence and early adulthood are the most susceptible phase of life for tobacco initiation and its use during this period can have profound public health implications. Anti-smoking campaigns have helped in reducing the social acceptability of smoking; however, newer nicotine products are becoming increasingly popular, globally. Evidence suggests that flavours play a key role in youth initiation of tobacco use. Flavoured Tobacco Products (FTP) are disproportionately used by the youth and young adults due to their high palatability and misperceptions regarding reduced ill effects of their constituents. Early use of a flavoured tobacco product puts youth and young adults at risk of continued tobacco use and other substance use. The prevalence of FTP use (72.7%) is much higher in young adults as compared to non-flavoured tobacco products.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Tabagismo , Adolescente , Adulto , Aromatizantes , Humanos , Uso de Tabaco/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: The Coronavirus disease (COVID-19) infection is caused by the novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) primarily affecting the lungs. All tobacco-related illnesses including asthma, chronic obstructive pulmonary disease (COPD), and coronary artery disease are known to reduce the lung capacity and impair the immune system of the body and can greatly influence the ability to fight the novel coronavirus. The purpose of this state-of-the-art literature review is to summarize the evidence of the association of tobacco use with the severity of the COVID-19 manifestations. METHOD: Articles describing the association of tobacco use with the severity of COVID-19 manifestations were searched on PubMed, MEDLINE, and Google. This review covers the relevant studies on the subject published from January 1, 2020 to September 10, 2020. RESULTS: Tobacco use in all forms, whether smoking or chewing, is significantly associated with severe COVID-19 outcomes. Pre-existing comorbidities in tobacco users such as cardiovascular diseases, diabetes, respiratory diseases and hypertension were found to further aggravate the disease manifestations making the treatment of such COVID-19 patients more challenging due to their rapid clinical deterioration. CONCLUSIONS: Current review indicates that nicotine exposure is linked to cardiopulmonary vulnerability to COVID-19 and tobacco use can be a potential risk factor for not only getting the viral infection but also its severe manifestations. The current pandemic provides a teachable moment to break the cycle of nicotine addiction and accelerate national tobacco control programs to achieve a tobacco-free world.
Assuntos
COVID-19/complicações , COVID-19/epidemiologia , Uso de Tabaco/efeitos adversos , Comportamentos Relacionados com a Saúde , Humanos , Fatores de RiscoRESUMO
AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism. METHODS: BI 705564 was studied in 2 placebo-controlled, Phase I clinical trials testing single-rising doses (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. RESULTS: All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. CONCLUSION: BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding-related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.
Assuntos
Linfócitos B , Agregação Plaquetária , Tirosina Quinase da Agamaglobulinemia , Voluntários Saudáveis , Humanos , Masculino , Inibidores de Proteínas Quinases/efeitos adversos , Transdução de SinaisRESUMO
Areca Nut (AN), the seed of tropical palm tree Areca catechu, is a widely chewed natural product with estimated 600 million users across the world. Various AN products, thriving in the market, portray 'Areca nut' or 'Supari' as mouth freshener and safe alternative to smokeless tobacco. Unfortunately, AN is identified as a Group 1 human carcinogen by International Agency for Research on Cancer (IARC). Wide variation in the level of alkaloids, broadly ranging from 2 to 10 mg/gm dry weight, is observed in diverse variety of AN sold worldwide. For the first time, various factors influencing the formation of carcinogenic alkaloids in AN at various stages, including during the growth, processing, and storage of the nut, are discussed. Current review illustrates the mechanism of cancer induction by areca alkaloids in humans and also compiles dose-dependent pharmacology and toxicology data of arecoline, the most potent carcinogenic alkaloid in AN. Careful monitoring of the arecoline content in AN can potentially be used as a tool in product surveillance studies to identify the variations in characteristics of various AN sample sold worldwide. The article will help to generate public awareness and sensitize the government bodies to initiate campaigns against AN use and addiction.
Assuntos
Alcaloides , Areca , Carcinógenos , Neoplasias/induzido quimicamente , Nozes , Alcaloides/farmacocinética , Alcaloides/farmacologia , Alcaloides/toxicidade , Animais , Areca/química , Carcinógenos/farmacocinética , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Relação Dose-Resposta a Droga , Humanos , Neoplasias/metabolismo , Nozes/químicaRESUMO
As the emergence of resistance to clinical cancer treatments poses a significant problem in cancer management, there is a constant need to explore novel anticancer agents which have the ability to overcome multidrug resistance (MDR) mechanisms. The search for the development of novel isatin-based antitumor agents accelerated after the approval by the Food and Drug Administration (FDA) of sunitinib malate, a C-3 isatin derivative, as a multitargeted receptor tyrosine kinase inhibitor. However, it is interesting to note that, over the last decade, various N-substituted analogs of isatin with intact carbonyl functionalities have been found to show more promising anticancer potential than its C-3 derivatives. Microtubule-targeting agents are a class of anticancer drugs which affect mitosis by targeting microtubules and suppressing their dynamic behavior. This review presents a systematic compilation of the in vitro cytotoxic and anticancer properties of various N-substituted isatins and illustrates their mechanism of action to overcome MDR by acting as microtubule-destabilizing agents. Predictions of the biological activities and cytotoxic effects of potential N-substituted isatins against various cancer cell lines have also been performed using the PASS computer-aided drug discovery program. Findings from such in vitro and in silico studies will act as a guide for the development of structure-activity relationship and will facilitate the design and exploration of more potent analogs of isatin with high potency and lower side effects for treatment of drug-resistant cancer. Mechanism of action of N-substituted isatin as microtubule-destabilizing agent on tumor cells. N-Substituted isatins bind to colchicine binding site on ß-tubulin, which inhibits microtubule polymerization and thereby destabilizes microtubule dynamics, resulting in mitotic arrest leading to tumor cell growth suppression.
Assuntos
Antineoplásicos/farmacologia , Simulação por Computador , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Isatina/farmacologia , Relação Quantitativa Estrutura-Atividade , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Técnicas In Vitro , Isatina/química , Microtúbulos/efeitos dos fármacosRESUMO
Due to the extensive ban on public smoking, tobacco companies focused their business on new smokeless tobacco (SLT) products promoting them as a harm reduction strategy and a safer alternative to cigarettes. Two nitrosamines, N'-nitrosonornicotine (NNN) and nicotine-derived nitrosamine ketone (NNK), present in SLT, listed as group 1 human carcinogens by the International Agency for Research on Cancer, are found to be the prime agents for most of cancers in SLT users. This review illustrates the mechanism of cancer induction by NNN and NNK in humans along with factors influencing the formation of NNN and NNK at various stages of tobacco manufacturing. It reveals the high levels and wide variations of NNN and NNK found among the diverse variety of SLT products sold worldwide. According to a recent report by FDA- Centre for Tobacco Products, reducing levels of nitrosamines in SLT products could greatly enhance the quality of life by reducing mortality, morbidity and medical expenditures due to cancer. For the first time, grass root approaches to minimize the levels of NNN and NNK in tobacco, from plant growth to the finished products, have been systematically compiled as they have the potential to contribute to reducing tobacco related disease burden.
Assuntos
Carcinógenos/análise , Nitrosaminas/análise , Indústria do Tabaco/métodos , Tabaco sem Fumaça/normas , Carcinógenos/química , Humanos , Neoplasias/etiologia , Nitrosaminas/química , Tabaco sem Fumaça/efeitos adversosRESUMO
As a result of the toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, the design and discovery of effective and selective antitumor agents continues to be a hot topic in organic medicinal chemistry. Targeted therapy is a newer type of cancer treatment that uses drugs designed to interfere with specific molecules necessary for tumor growth and progression. This review explains the mechanism of regulation of p53 (tumor suppressor protein) by MDM2 and illustrates the role of targeting p53-MDM2 protein-protein interaction using small molecules as a new cancer therapeutic strategy. Spirocyclic oxindoles or spiro-oxindoles, with a rigid heterocyclic ring fused at the 3-position of the oxindole core with varied substitution around it, are the most efficacious class of small molecules which inhibit cell proliferation and induce apoptosis in cancer cells, leading to complete tumor growth regression without affecting activities of normal cells. In this review, we present a comprehensive account of the systematic development of and recent progress in diverse spiro-oxindole derivatives active as potent selective inhibitors of p53-MDM2 interaction with special emphasis on spiro-pyrrolidinyl oxindoles (the MI series), their mechanism of action, and structure-activity relationship. This review will help in understanding the molecular mechanism of p53 reactivation by spiro-oxindoles in tumor tissues and also facilitates the design and exploration of more potent analogues with high efficacy and low side effects for the treatment of cancer. Recent progress in spiro-oxindole derivatives as potent small molecule inhibitors of p53-MDM2 interaction, useful as anticancer agents, is described with reference to their mechanism of action and structure-activity relationship.
Assuntos
Neoplasias/tratamento farmacológico , Oxindóis/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Compostos de Espiro/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Humanos , Conformação Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Oxindóis/química , Proteínas Proto-Oncogênicas c-mdm2/química , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Bibliotecas de Moléculas Pequenas/química , Compostos de Espiro/química , Proteína Supressora de Tumor p53/química , Proteína Supressora de Tumor p53/metabolismoRESUMO
Background: Though people of color (POC) are less likely to become afflicted with skin cancer, they are much more likely to die from it due to delay in detection or presentation. Very often, skin cancer is diagnosed at a more advanced stage in POC, making treatment difficult.The purpose of this research was to improve awareness regarding skin cancers in people of color by providing recommendations to clinicians and the general public for early detection and photo protection preventive measures. Methods: Data on different types of skin cancers were presented to POC. Due to limited research, there are few resources providing insights for evaluating darkly pigmented lesions in POC. Diagnostic features for different types of skin cancers were recorded and various possible risk factors were considered. Results: This study provided directions for the prevention and early detection of skin cancer in POC based on a comprehensive review of available data. Conclusions: The increased morbidity and mortality rate associated with skin cancer in POC is due to lack of awareness, diagnosis at a more advanced stage and socioeconomic barriers hindering access to care. Raising public health concerns for skin cancer prevention strategies for all people, regardless of ethnic background and socioeconomic status, is the key to timely diagnosis and treatment.