Mechanisms of Cancer Induction by Tobacco-Specific NNK and NNN

Abstract

Tobacco use is a major public health problem worldwide. Tobacco-related cancers cause millions of deaths annually. Although several tobacco agents play a role in the development of tumors, the potent effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) are unique. Metabolically activated NNK and NNN induce deleterious mutations in oncogenes and tumor suppression genes by forming DNA adducts, which could be considered as tumor initiation. Meanwhile, the binding of NNK and NNN to the nicotinic acetylcholine receptor promotes tumor growth by enhancing and deregulating cell proliferation, survival, migration, and invasion, thereby creating a microenvironment for tumor growth. These two unique aspects of NNK and NNN synergistically induce cancers in tobacco-exposed individuals. This review will discuss various types of tobacco products and tobacco-related cancers, as well as the molecular mechanisms by which nitrosamines, such as NNK and NNN, induce cancer.

Electronic cigarettes—A review of the physiological health effects

“…For example, Kim and Shin (2013) found an average of 12.99 ± 18.23 μg/L of these toxicants in 105 EC liquids from Korean shops. TSNAs are derived from tobacco leaves and are very potent carcinogens due to their ability to form DNA adducts, inhibiting tumour suppressor genes and activating oncogenes (Xue et al 2014). Because ECs do not contain tobacco, they should not contain TSNAs, which indicates that their presence is the result of nicotine contaminants (Farsalinos et al 2015a).…”

Antioxidant and free radical scavenging activities of Viola odorata in the search of potential inhibitor of tobaccos free radicals

“…Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License NNK and NNN cause cancer by deoxyribonucleic acid (DNA) adductions and mutations by receptor-mediated effect on tumor growth (Xue et al, 2014;Takahashi et al, 2010). Tobacco smokes contains free radicals which induce oxidative damage or stress (Valko et al, 2006).…”

“…According to the World Health Organization, one out of two people smoking throughout their lives will end up having TRC (WHO, 2012). In addition to nicotine, tobacco mainly contains polyaromatic hydrocarbons (PAH) and Nnitrosamine carcinogens (Xue et al, 2014). The tobacco specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), are carcinogenic to humans (IARC, 2007).…”

“…The tobacco smoke has large amounts of nitric oxide and other unstable oxidants like hydroquinones, semiquinones and quinones (Xue et al, 2014;Hecht, 2003). These compounds induce redox cycling and are responsible for oxidative damage (Hecht, 2011;Pryor et al, 1998).…”

The Association Between Epoxide Hydrolase Genetic Variant and Effectiveness of Nicotine Replacement Therapy in a Han Chinese Population

“…Pharmacological treatment, such as nicotine replacement therapy (NRT), is a valid solution to this problem. Tobacco smoke contains many carcinogens such as nitrosamines [i.e., nicotinederived nitrosamine ketone (NNK) and N-nitrosonornicotine (NNN)], and nicotine undergoes chemical conversion into NNK and NNN during the processes of curing and smoking [3]. Microsomal epoxide hydrolase (EPHX) is responsible for the metabolism of polycyclic aromatic hydrocarbons and the detoxification of pro-carcinogens in the process of smoking [4].…”