Chronic nicotine inhibits the therapeutic effects of gemcitabine on pancreatic cancer in vitro and in mouse xenografts
Experimental Oncology Laboratory, Department of Biomedical & Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA. European journal of cancer (Oxford, England: 1990)
(Impact Factor: 5.42).
11/2012; 49(5). DOI: 10.1016/j.ejca.2012.10.015
Aim of study:
Smoking is an established risk factor for pancreatic cancer and nicotine replacement therapy (NRT) often accompanies chemotherapy. The current study has tested the hypothesis that chronic exposure to low dose nicotine reduces the responsiveness of pancreatic cancer to the leading therapeutic for this cancer, gemcitabine.
The effects of chronic nicotine (1 μm/L) on two pancreatic cancer cell lines in vitro and in a xenograft model were assessed by immunoassays, Western blots and cell proliferation assays.
Exposure in vitro to nicotine for 7 days inhibited the gemcitabine-induced reduction in viable cells, gemcitabine-induced apoptosis as indicated by reduced expression of cleaved caspase-3 while inducing the phosphorylation of signalling proteins extracellular signal-regulated kinase (ERK), v-akt thymoma viral oncogene homolog (protein kinase B, AKT) and Src. Nicotine (1 μm/L) in the drinking water for 4 weeks significantly reduced the therapeutic response of mouse xenografts to gemcitabine while reducing the induction of cleaved caspase-3 and the inhibition of phosphorylated forms of multiple signalling proteins by gemcitabine in xenograft tissues.
Our experimental data suggest that continued moderate smoking and NRT may negatively impact therapeutic outcomes of gemcitabine on pancreatic cancer and that clinical studies in cancer patients are now warranted.
Available from: Lubomir Svorc
- "Chemically, NIC is a pyridine alkaloid representing one of more than 4000 constituents of tobacco smoke, such as carbon monoxide, tar, formaldehyde and benzene . Hence, tobacco smoke is harmful to both types of smokers, active and passive, and often causes cancer of various organs involving lung, nose, oral cavity, kidney, stomach, bladder and colon  . NIC acts on the central nervous system in the form of elevation of mood, sense of euphoria and revitalizing energy . "
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ABSTRACT: A sensitive, selective and reliable electrochemical method for the determination of nicotine using differential
pulse voltammetry on a bare boron-doped diamond electrode has been developed. Nicotine yielded a single
oxidation peak at a highly positive potential of +1.45 V (vs. Ag/AgCl/3 M KCl) in Britton–Robinson buffer solution at pH 8. The inﬂuence of supporting electrolyte, pH and scan rate on the current response of NIC was investigated. At optimized experimental conditions, a linear relation between peak current and concentration of nicotine was found for the range from 0.5 to 200 μM (0.08–32.9 mg L−1) with a detection limit of 0.3 μM (0.05 mg L−1) and a good repeatability (relative standard deviation of 2.1% at 25 μM concentration level, n = 10) was achieved without any electrode surface modiﬁcation. The practical usefulness of the developed procedure was successfully demonstrated with the determination of nicotine in tobacco products and anti-smoking pharmaceuticals with results similar to those obtained by a high-performance liquid chromatography and to the contents declared by the manufacturer, respectively. Prior to analysis, the sample pretreatment includes only sonication and/or simple liquid–liquid extraction. The proposed sensor represents an effective electrochemical tool and a promising alternative for quality control analysis of products in tobacco and pharmaceutical industry.
Available from: Hildegard Schuller
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ABSTRACT: Smoking has been extensively documented as a risk factor for all histological types of lung cancer and tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons reproducibly cause lung cancer in laboratory rodents. However, the most common lung cancer, non-small cell lung cancer (NSCLC), frequently develops in never smokers and is particularly common in women and African Americans, suggesting that factors unrelated to smoking significantly impact this cancer. Recent experimental investigations in vitro and in animal models have shown that chronic psychological stress and the associated hyperactive signaling of stress neurotransmitters via β-adrenergic receptors significantly promote the growth and metastatic potential of NSCLC. These responses were caused by modulation in the expression and sensitization state of nicotinic acetylcholine receptors (nAChRs) that regulate the production of stress neurotransmitters and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Similar changes in nAChR-mediated neurotransmitter production were identified as the cause of NSCLC stimulation in vitro and in xenograft models by chronic nicotine. Collectively, these data suggest that hyperactivity of the sympathetic branch of the autonomic nervous system caused by chronic psychological stress or chronic exposure to nicotinic agonists in cigarette smoke significantly contribute to the development and progression of NSCLC. A recent clinical study that reported improved survival outcomes with the incidental use of β-blockers among patients with NSCLC supports this interpretation.
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ABSTRACT: This Opinion article discusses emerging evidence of direct contributions of nicotine to cancer onset and growth. The list of cancers reportedly connected to nicotine is expanding and presently includes small-cell and non-small-cell lung carcinomas, as well as head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and kidney cancers. The mutagenic and tumour-promoting activities of nicotine may result from its ability to damage the genome, disrupt cellular metabolic processes, and facilitate growth and spreading of transformed cells. The nicotinic acetylcholine receptors (nAChRs), which are activated by nicotine, can activate several signalling pathways that can have tumorigenic effects, and these receptors might be able to be targeted for cancer therapy or prevention. There is also growing evidence that the unique genetic makeup of an individual, such as polymorphisms in genes encoding nAChR subunits, might influence the susceptibility of that individual to the pathobiological effects of nicotine. The emerging knowledge about the carcinogenic mechanisms of nicotine action should be considered during the evaluation of regulations on nicotine product manufacturing, distribution and marketing.
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