Genotoxicity Study on Nicotine and Nicotine-Derived Nitrosamine by Accelerator Mass Spectrometry

Li, X. S.; Wang, Haifang; Shi, J. Y.; Wang, X. Y.; Liu, Y. F.; Li, K.; Lu, Xuesong; Wang, J. J.; Liu, K. X.; Guo, Zhiqiang

doi:10.1017/s0033822200017677

Cited by 25 publications

(13 citation statements)

References 15 publications

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“…Previous studies have implied that nicotine may be genotoxic, forming adducts with DNA, histone H1͞H3, or H1b, thereby causing mutations in vital genes leading to neoplastic transformation (4,5). However, recent evidence has shown that nicotine can also lead to sustained activation of mitogenic pathways, promote angiogenesis, and accelerate tumor growth and atherosclerosis (6)(7)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 99%

Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin

Dasgupta

Kinkade

Joshi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

280

263

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Non-small cell lung cancer (NSCLC) demonstrates a strong etiologic association with smoking. Although nicotine is not carcinogenic, it can induce cell proliferation and angiogenesis and suppress apoptosis induced by certain agents. Here we show that nicotine inhibits apoptosis induced by the drugs gemcitabine, cisplatin, and taxol, which are used to treat NSCLCs. This protection correlated with the induction of XIAP and survivin by nicotine in a panel of human NSCLC cell lines, and depletion of XIAP and survivin ablated the protective effects of nicotine. The antiapoptotic effects of nicotine were mediated by dihydro ␤-erythroidine-sensitive ␣3-containing nicotinic acetylcholine receptors and required the Akt pathway. Chromatin immunoprecipitation assays demonstrated that nicotine stimulation caused an increased recruitment of E2F1 and concomitant dissociation of retinoblastoma tumor suppressor protein (Rb) from survivin promoter in A549 cells. Moreover, ablation of E2F1 levels caused abrogation of the protective effects of nicotine against cisplatin-induced apoptosis in A549 cells whereas ablation of signal transducer and activator of transcription 3 levels had no effect. These studies suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that survivin and XIAP play a key role in the antiapoptotic activity of nicotine.E2F ͉ retinoblastoma ͉ Stat 3 ͉ IAP ͉ lung cancer C igarette smoking is a major risk factor in the development of non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers (1-3). Previous studies have implied that nicotine may be genotoxic, forming adducts with DNA, histone H1͞H3, or H1b, thereby causing mutations in vital genes leading to neoplastic transformation (4, 5). However, recent evidence has shown that nicotine can also lead to sustained activation of mitogenic pathways, promote angiogenesis, and accelerate tumor growth and atherosclerosis (6-13). Nicotine and its related carcinogens, like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, have been found to activate Raf-1-, EGFR-, c-Src-, Akt-, and 5-lipooxygenase-mediated growth stimulatory pathways (14-19). In addition, nicotine has been also found to inhibit apoptosis induced by opioids, etoposide, cisplatin, and UV irradiation in lung cancer cells (7,10,14). The inhibitory effect of nicotine on apoptosis has been attributed to its ability to activate and phosphorylate antiapoptotic proteins like Bcl-2, induction of NF-B complexes, activation of the Akt pathway, as well as inactivation of proapoptotic proteins like Bax and Bad through phosphorylation in lung cancer cells (7,(20)(21)(22)(23)(24).NSCLC is characterized by its poor prognosis and resistance to the apoptotic activity of antineoplastic drugs both in vivo and in vitro (25,26). Although many signaling cascades have been implicated in the acquisition of chemoresistance in NSCLC (3, 26, 27), we conjectured that it is probable that the antiapoptotic effects of nicotine contribute to the process. Here we...

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mentioning

confidence: 99%

Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin

Dasgupta

Kinkade

Joshi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

280

263

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“…It was implied that nicotine might be genotoxic based on the fact that large doses of nicotine could significantly increase mutation frequency and sister chromatid exchange frequency in cellular experiments (Riebe and Westphal, 1983;Trivedi et al, 1999). Li et al reported that nicotine could form adducts with mouse liver DNA, lung DNA, histone H1/H3, Hb, and albumin in mice and demonstrated a positive relationship between dose and adduction (Li et al, 1996;Wu et al, 1997), whereas DNA adducts have been widely accepted as biomarkers for the dosimetry of chemical carcinogens. Furthermore, Pratesi et al and others reported that nicotine stimulated the growth of human small cell lung cancer cells (Cattaneo et al, 1993;Codignola et al, 1994;Pratesi et al, 1996).…”

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confidence: 99%

Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway

Ye¹,

Liu²,

Shin³

et al. 2003

J Pharmacol Exp Ther

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Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco, has been implicated as playing a role in carcinogenesis. Our previous study showed that passive cigarette smoking promoted inflammation-associated colonic adenoma formation in mice, and 5-lipoxygenase (5-LOX) plays an important role in this process. In the present study, we aimed to investigate whether nicotine could stimulate colon cancer cell proliferation and tumor growth in nude mice xenograft model and the possible mechanisms involved. Results showed that nicotine stimulated SW1116 colon cancer cell proliferation in a dose-dependent manner. Epidermal growth factor receptor (EGFR) and c-Src phosphorylation levels together with protein expression of 5-LOX were also significantly enhanced in this proliferation process. Inhibitors of EGFR and c-Src alleviated the actions of nicotine on cell proliferation and 5-LOX protein expression. Combination of both agents produced additive effect. In contrast, 5-LOX inhibitor had no direct effect on the phosphorylation levels of EGFR and c-Src and yet inhibited cell proliferation. In the colon cancer xenograft model, nicotine also significantly enhanced tumor growth. This acceleration of tumor growth corresponded well with increased vascularization and its proangiogenic factors. Inhibitors of EGFR, c-Src, and 5-LOX all significantly impeded the tumor growth induced by nicotine. Together, nicotine can promote colonic tumorigenesis both in vitro and in vivo. Activation of the phosphorylated form of EGFR and c-Src followed by an increased 5-LOX expression are the prime pathogenic mechanisms in the tumorigenic process in the colon.

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“…Nicotine, previously demonstrated to have no association between its exposure and induction of Leydig cell hyperplasia or adenomas in humans, was able to induce Leydig cell tumor in rats (71). Experiment utilizing the ultrasensitive method of accelerator mass spectrometry also showed that nicotine could dose-dependently form adducts with liver DNA, lung DNA, histone H1 / H3, Hb, and albumin in mice (72,73). The formation of DNA adduct plays a crucial role in chemical carcinogenesis.…”

Section: Mutagenicitymentioning

confidence: 97%

The Pharmacological Actions of Nicotine on the Gastrointestinal Tract

Cho

2004

J Pharmacol Sci

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Abstract. Increasing use of tobacco and its related health problems are a great concern in the world. Recent epidemiological findings have demonstrated the positive association between cigarette smoking and several gastrointestinal (GI) diseases, including peptic ulcer and cancers. Interestingly, smoking also modifies the disease course of ulcerative colitis (UC). Nicotine, a major component of cigarette smoke, seems to mediate some of the actions of cigarette smoking on the pathogenesis of GI disorders. Nicotine worsens the detrimental effects of aggressive factors and attenuates the protective actions of defensive factors in the processes of development and repair of gastric ulceration. Nicotine also takes part in the initiation and promotion of carcinogenesis in the GI tract. In this regard, nicotine and its metabolites are found to be mutagenic and have the ability to modulate cell proliferation, apoptosis, and angiogenesis during tumoriogenesis through specific receptors and signalling pathways. However, to elucidate this complex pathogenic mechanism, further study at the molecular level is warranted. In contrast, findings of clinical trials give promising results on the use of nicotine as an adjuvant therapy for UC. The beneficial effect of nicotine on UC seems to be mediated through multiple mechanisms. More clinical studies are needed to establish the therapeutic value of nicotine in this disease.

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Genotoxicity Study on Nicotine and Nicotine-Derived Nitrosamine by Accelerator Mass Spectrometry

Cited by 25 publications

References 15 publications

Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin

Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin

Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway

The Pharmacological Actions of Nicotine on the Gastrointestinal Tract

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