Mechanistic Approaches To The Prevention Of Mutation And Cancer

Cancer and other mutation-related diseases can be prevented at three levels: primary prevention, which is addressed to healthy individuals in order to prevent occurrence of the disease; secondary prevention, which is addressed to early stage patients in order to prevent progression of the disease; and tertiary prevention, which is addressed to patients after therapy in order to prevent relapses of the disease. Although the most obvious approach to prevention is to minimize exposures to recognized risk factors, a complementary strategy is represented by chemoprevention, using dietary and pharmacological agents that reinforce the host defence machinery. Since 1988, I proposed detailed classifications of mechanisms of inhibitors of mutagenesis and carcinogenesis. They may apply not only to cancer but also to other degenerative diseases that have replaced infectious diseases as the leading causes of death in the population. In fact, certain mechanisms, such as damage to nuclear DNA and mtDNA, oxidative stress, chronic inflammation, signal transduction alterations and epigenetic changes may be involved in the pathogenesis of different diseases. Studies performed in our laboratory have shown that certain genomic alterations that are usually investigated in cancer research may also be detected in other chronic diseases, such as atherosclerosis, degenerative heart diseases, chronic obstructive pulmonary diseases, neurological disorders, eye diseases, skin ageing, and alopecia. Similar alterations were investigated in critical periods of life, such as birth and ageing. The nucleotide alterations occurring at birth in the lung render the newborn particularly vulnerable to the action of environmental agents. In fact, we demonstrated that cigarette smoke becomes a potent carcinogen in mice when exposure starts at birth and continues early in life. We investigated a number of chemopreventive agents by evaluating modulation of intermediate biomarkers and carcinogenicity. An optimal agent should not excessively alter the physiological patterns of gene expression, microRNA and proteome profiles, but at the same time it should be effective in inhibiting alterations induced by mutagens and carcinogens. It should be noted that most chemopreventive agents possess pleiotropic properties. The knowledge of mechanisms can be exploited to combine different agents working with complementary mechanisms. Like the therapy of important diseases, such as cancer, cardiovascular diseases, AIDS, etc., uses combinations of drugs, combined chemoprevention is a quite promising strategy. Although a large number of agents are potentially able to prevent cancer, we are in search of tools to predict, hopefully in the single individual, their efficacy and safety in humans

Mechanisms Of Inhibition Of Cigarette Smoke Genotoxicity And Carcinogenicity

Epidemiological studies have demonstrated that it is possible to prevent lung cancer and other smoke-related diseases by avoiding exposures to tobacco smoke. A complementary strategy is chemoprevention, which is based on the administration of dietary and pharmacological agents, which is addressed to (a) addicted active smokers, who are unable to quit smoking, (b) ex-smokers, who are still at risk for several years, and (c) involuntary smokers, including passively exposed individuals as well as transplacentally exposed individuals. The biological effects of cigarette smoke (CS) as a complex mixture, either mainstream (MCS) or sidestream (SCS) or environmental (ECS), have been poorly explored. We showed that MCS and ECS induce a broad variety of alterations of intermediate biomarkers in animal models, including adducts to nuclear DNA and mtDNA, oxidatively generated DNA damage, proliferation, apoptosis, alterations of oncogenes and tumor suppressor genes, multigene expression, microRNA and proteome profiles as well as cytogenetic damage in the respiratory tract, bone marrow and peripheral blood. CS-altered end-points were variously modulated by chemopreventive agents of natural or pharmacological origin, such as N-acetyl-L-cysteine (NAC), 1,2-dithiole-3-thione, oltipraz, 5,6-benzoflavone, phenethyl isothiocyanate (PEITC), indole-3-carbinol, sulindac, and budesonide. Combinations of agents were also assayed. Since it is difficult to assess the efficacy of chemopreventives in clinical trials, it is essential to understand the mechanisms by which certain agents are expected to prevent smoke-related cancer. Preclinical studies are also useful to demonstrate the potential efficacy of chemopreventive agents. Unfortunately, until recently a suitable animal model for evaluating CS carcinogenicity and its chemoprevention was not available. We demonstrated that ECS and especially MCS become potently carcinogenic when exposure of mice starts at birth, as shown by very short latency times, high incidence and multiplicity of benign lung tumors, early occurrence of malignant lung tumors, and lesions in other organs. This mouse model was successfully used to demonstrate the ability of NAC, PEITC, and budesonide to prevent smoke-induced lung cancer, according to protocols mimicking the situation either in current smokers or in ex-smokers. Other dietary or pharmacological agents, including curcumin, anthocyanins, myo-inositol, SAHA, bexarotene and pioglitazone, are now under study. NAC was even successful to prevent lung cancer induced by MCS after birth when it was administered during the prenatal life. Therefore, it is now possible to investigate in vivo not only alterations of intermediate biomarkers but also the modulation of CS carcinogenesis by chemopreventive agents working with different mechanisms

Epidemiology of cancers of infectious origin and prevention strategies

Infectious and parasitic diseases represent the third cause of cancer worldwide. A number of infectious and parasitic agents have been suspected or recognized to be associated with human cancers, including DNA viruses, such as papillomaviruses (several HPV types), herpesviruses (EBV and KSHV), polyomaviruses (SV40, MCV, BK, and JCV), and hepadnaviruses (HBV); RNA viruses, such as flaviviruses (HCV), defective viruses (HDV), and retroviruses (HTLV-I, HTLV-II, HIV-1, HIV-2,HERV-K, and XMRV); bacteria, such as H. pylori, S. typhi, S. bovis, Bartonella, and C. pneumoniae; protozoa, such as P. falciparum; trematodes, such as S. haematobium, S. japonicum, S. mansoni, O. viverrini, O. felineus, and C. sinensis. Each one of the chronic infections with H. pylori, HPV, and HBV/HCV is responsible for approximately the 5% of all human cancers. The primary prevention of infection-related cancers is addressed both to avoidance and eradication of chronic infections and to protection of the host organism. Vaccines provide fundamental tools for the prevention of infectious diseases and related cancers. The large-scale application of the HBV vaccine has already shown to favorably affect the epidemiological burden of primary hepatocellular carcinoma, and HPV vaccines have specifically been designed in order to prevent cervical cancer and other HPV-related cancers. The secondary prevention of infection-associated cancers has already found broad applications in the control of cervical cancer. Detection of early gastric cancer by endoscopy has been applied in Asian countries. Avoidance of local relapses, invasion, and metastasis may be achieved by applying tertiary prevention, which targets specific mechanisms, such as angiogenesis

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor

Chronic inflammation plays a crucial role in the carcinogenesis process and in particular in smoking-related carcinogenesis. Therefore, anti-inflammatory agents provide an interesting perspective in the prevention of smoking-associated cancers. Among nonsteroidal anti-inflammatory drugs (NSAIDs), licofelone is a triple inhibitor of both cyclooxygenases (COX-1 and COX-2) and of 5-lipooxygenase (5-LOX) that has shown some encouraging results in cancer prevention models. We previously showed that the dietary administration of licofelone, starting after weanling, to Swiss H mice exposed for 4 months to mainstream cigarette smoke since birth attenuated preneoplastic lesions of inflammatory nature in both lung and urinary tract, and had some effects on the yield of lung tumors at 7.5 months of age. The present study aimed at evaluating the early modulation by licofelone of pulmonary DNA and RNA alterations either in smoke-free or smoke-exposed H mice after 10 weeks of exposure. Licofelone protected the mice from the smoke-induced loss of body weight and significantly attenuated smoke-induced nucleotide alterations by decreasing the levels of bulky DNA adducts and 8-hydroxy-2'-deoxyguanosine in mouse lung. Moreover, the drug counteracted dysregulation by smoke of several pulmonary microRNAs involved in stress response, inflammation, apoptosis, and oncogene suppression. However, even in smoke-free mice administration of the drug had significant effects on a broad panel of microRNAs and, as assessed in a subset of mice used in a parallel cancer chemoprevention study, licofelone even enhanced the smoke-induced systemic genotoxic damage after 4 months of exposure. Therefore, caution should be paid when administering licofelone to smokers for long periods

Estimates of the incidence of infection-related cancers in Italy and Italian regions in 2018

Introduction. Chronic infections and infestations represent one of the leading causes of cancer. Eleven agents have been categorized by the International Agency for Research on Cancer (IARC) in Group 1, 3 in Group 2A and 4 in Group 2B. We previously estimated that the incidence of cancers associated with infectious agents accounted for the 8.5% of new cancer cases diagnosed in Italy in 2014. Methods. In the present study we evaluated the incidence of cancer in Italy and in the 20 Italian regions in 2018, based on the data of Cancer Registries, and calculated the fraction attributable to infectious agents. Results. Cancers of infectious origin contributed to the overall burden of cancer in Italy with more than 27,000 yearly cases, the 92% of which was attributable to Helicobacter pylori, human papillomaviruses, and hepatitis B and C viruses. With the exception of papillomavirus-related cancers, the incidence of cancers of infectious origin was higher in males (16,000 cases) than in females (11,000 cases). There were regional and geographical variations of cancers depending on the type of cancer and on the gender. Nevertheless, the overall figures were rather similar, the infection-related cancers accounting for the 7.2, 7.6, and 7.1% of all cancers in Northern, Central, and Southern Italy, respectively. Conclusions. The estimate of the incidence of cancers attributable to infectious agents in Italy in 2018 (7.3% of all cancer cases) is approximately half of the worldwide burden, which has been estimated by IARC to be the 15.4% of all cancer cases in 2012

Modulation of genomic and epigenetic end-points by celecoxib

Celecoxib, a nonsteroidal anti-inflammatory drug that selectively targets cyclooxygenase-2, is a promising cancer chemopreventive agent. However, safety concerns have been raised in clinical trials evaluating its ability to prevent colorectal adenomas. The rationale for the herein reported studies was to analyze genomic and epigenetic end-points aimed at investigating both the chemopreventive properties of celecoxib towards cigarette smoke-associated molecular alterations and its possible adverse effects. We carried out three consecutive studies in mice treated with either smoke and/or celecoxib. Study 1 investigated early DNA alterations (DNA adducts, oxidative DNA damage, and systemic genotoxic damage) and epigenetic alterations (expression of 1,135 microRNAs) in lung and blood of Swiss H mice; Study 2 evaluated the formation of DNA adducts in lung, liver, and heart; and Study 3 evaluated the expression of microRNAs in 10 organs and 3 body fluids of ICR (CD-1) mice. Surprisingly, the oral administration of celecoxib to smoke-free mice resulted in the formation of DNA adducts in both lung and heart and in dysregulation of microRNAs in mouse organs and body fluids. On the other hand, celecoxib attenuated smoke-related DNA damage and dysregulation of microRNA expression. In conclusion, celecoxib showed pleiotropic properties and multiple mechanisms by counteracting the molecular damage produced by smoke in a variety of organs and body fluids. However, administration of celecoxib to non-smoking mice resulted in evident molecular alterations, also including DNA and RNA alterations in the heart, which may bear relevance in the pathogenesis of the cardiovascular adverse effects of this drug

Reduction of hexavalent chromium by fasted and fed human gastric fluid. I. Chemical reduction and mitigation of mutagenicity

Abstract Evaluation of the reducing capacity of human gastric fluid from healthy individuals, under fasted and fed conditions, is critical for assessing the cancer hazard posed by ingested hexavalent chromium [Cr(VI)] and for developing quantitative physiologically-based pharmacokinetic models used in risk assessment. In the present study, the patterns of Cr(VI) reduction were evaluated in 16 paired pre- and post-meal gastric fluid samples collected from 8 healthy volunteers. Human gastric fluid was effective both in reducing Cr(VI), as measured by using the s-diphenylcarbazide colorimetric method, and in attenuating mutagenicity in the Ames test. The mean (± SE) Cr(VI)-reducing ability of post-meal samples (20.4 ± 2.6 μg Cr(VI)/mL gastric fluid) was significantly higher than that of pre-meal samples (10.2 ± 2.3 μg Cr(VI)/mL gastric fluid). When using the mutagenicity assay, the decrease of mutagenicity produced by pre-meal and post-meal samples corresponded to reduction of 13.3 ± 1.9 and 25.6 ± 2.8 μg Cr(VI)/mL gastric fluid, respectively. These data are comparable to parallel results conducted by using speciated isotope dilution mass spectrometry. Cr(VI) reduction was rapid, with > 70% of total reduction occurring within 1 min and 98% of reduction is achieved within 30 min with post-meal gastric fluid at pH 2.0. pH dependence was observed with decreasing Cr(VI) reducing capacity at higher pH. Attenuation of the mutagenic response is consistent with the lack of DNA damage observed in the gastrointestinal tract of rodents following administration of ≤ 180 ppm Cr(VI) for up to 90 days in drinking water. Quantifying Cr(VI) reduction kinetics in the human gastrointestinal tract is necessary for assessing the potential hazards posed by Cr(VI) in drinking water