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Acetylcholine Receptor Pathway and Lung Cancer

      Abstract:

      Genome-wide association studies revealed chromosome regions 15q24-25 were associated with a higher risk for development of lung cancer. The 15q24-25 region encompasses the nicotinic acetylcholine receptor subunit genes (nAchR ±3, ±5, and ²4) that play a role in nicotine addiction. This review reports information of the acetylcholine receptor and lung cancer. In patients diagnosed with smoking-related lung cancer and who continue smoking, a negative correlation with lung cancer survival has been shown. The reduced treatment efficacy may well be explained by the pluriform effect of nicotine on tumor cell proliferation, apoptosis, epithelialmesenchymal transition, proinvasive, and angiogenic effects, which are reenforced by an autocrine/paracrine loop. Overall, there is no evidence that nicotine itself induces cancer, but nicotine promotes in vivo the growth of cancer cells and the proliferation of endothelial cells. This suggests that nicotine after initiation may contribute to the progression phase of cancer development. Continuation of smoking after lung cancer has been diagnosed should be discouraged because smoking may not only support tumor growth but also interferes with treatment.

      Keywords

      This overview aims at providing insight on the acetylcholine receptor (AchR) pathway in lung cancer. Genome-wide association studies provide a powerful approach to identify common, low-penetrance disease loci without prior knowledge of their location or function.
      • Easton DF
      • Eeles RA
      Genome-wide association studies in cancer.
      Chromosome regions 15q24-25,
      • Hung RJ
      • McKay JD
      • Gaborieau V
      • et al.
      A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.
      • Liu P
      • Vikis HG
      • Wang D
      • et al.
      Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer.
      15q15.33,
      • McKay JD
      • Hung RJ
      • Gaborieau V
      • et al.
      Lung cancer susceptibility locus at 5p15.33.
      and 6p21.33
      • Wang Y
      • Broderick P
      • Webb E
      • et al.
      Common 5p15.33 and 6p21.33 variants influence lung cancer risk.
      seem to have common sequence variants that may convey a higher risk for developing lung cancer. The odds ratios associated with these variants are generally between 1.2 and 1.5, denoting a definite but relatively weak association and support the supposition that susceptibility to lung cancer is polygenic. The 15q24-25 region encompasses the nicotinic acetylcholine receptor subunit genes (nAchR ±3, ±5, and ²4), which play a role in nicotine addiction.
      • Spitz MR
      • Amos CI
      • Dong Q
      • Lin J
      • Wu X
      The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.
      • Weiss RB
      • Baker TB
      • Cannon DS
      • et al.
      A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction.
      Two types of AchRs exist. The nAchR and muscarinic AchR (mAchR). The nAchR is a pentamer consisting of four related but genetically and immunologically distinct subunits. After assembly, the protein contains two ± subunits, and one of each ², γ, and δ subunits.
      • Albuquerque EX
      • Pereira EF
      • Alkondon M
      • Rogers SW
      Mammalian nicotinic acetylcholine receptors: from structure to function.
      Although in theory many different combinations of subunits exists, only a minority are detected in practice. Factors influencing the assembly are essentially unknown. The nAchR is a Ca++ or Na+ ion channel. The ratio of Ca++ to Na+ exchange depends on the AchR subtype, the ±7 subtype has the largest Ca++ to Na+ ratio.
      The mAchR receptor belongs to the family of G-protein coupled receptors with seven transmembrane spanning domains and has five subtypes (M1-M5). Similar to nAchR, mAchR is also a protein assembled with genetically distinct subunits. The M1, M3, and M5 subtypes have been linked to cell proliferation and are coupled with Gq, and on activation lead to increased levels of intracellularinositol triphosphate, diacylglycerol, and Ca++. The M2 and M4 receptors are coupled to Gi and inhibit adenylyl cyclase formation.
      • Wess J
      Molecular biology of muscarinic acetylcholine receptors.
      People who start smoking at an earlier age run a greater risk for long-term nicotine addiction. Recently, it was shown that in three different cohorts of long-term smokers with early nicotine exposure (before the age of 17 years), the ChRN±5-±3-²4 haplotypes were related to the severity of nicotine dependence. Other haplotypes were protective or neutral for dependence of nicotine.
      • Weiss RB
      • Baker TB
      • Cannon DS
      • et al.
      A candidate gene approach identifies the CHRNA5-A3-B4 region as a risk factor for age-dependent nicotine addiction.
      The ±5-±3 subtype nAchR association of smoking and lung cancer was specific for lung cancer because no evidence for elevated risk was found in never smoking patients with lung cancer or for other smoking-related cancer types (bladder and kidney).
      • Spitz MR
      • Amos CI
      • Dong Q
      • Lin J
      • Wu X
      The CHRNA5-A3 region on chromosome 15q24-25.1 is a risk factor both for nicotine dependence and for lung cancer.
      The identification of an age- and smoking-dependent susceptibility haplotype reinforces the importance of preventing early exposure to tobacco through public health policies.

      BRONCHIAL EPITHELIAL CELLS

      Acetylcholine (Ach) is produced and degraded in airway epithelial cells.
      • Klapproth H
      • Reinheimer T
      • Metzen J
      • et al.
      Non-neuronal acetylcholine, a signalling molecule synthezised by surface cells of rat and man.
      • Proskocil BJ
      • Sekhon HS
      • Jia Y
      • et al.
      Acetylcholine is an autocrine or paracrine hormone synthesized and secreted by airway bronchial epithelial cells.
      Human bronchial epithelium (HBE) selectively expresses ±3, ±5, ±7, ²2, and ²4 subunits of the nAchR genes.
      • Maus AD
      • Pereira EF
      • Karachunski PI
      • et al.
      Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors.
      • Zia S
      • Ndoye A
      • Nguyen VT
      • Grando SA
      Nicotine enhances expression of the alpha 3, alpha 4, alpha 5, and alpha 7 nicotinic receptors modulating calcium metabolism and regulating adhesion and motility of respiratory epithelial cells.
      • Plummer III, HK
      • Dhar M
      • Schuller HM
      Expression of the alpha7 nicotinic acetylcholine receptor in human lung cells.
      Nicotine and the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(-3-pyridine)-1-butanone (NNK), are agonists for the nAchRs. Remarkably, the affinity of nicotine is greater than for the physiological agonist, Ach.
      • Schuller HM
      Nitrosamines as nicotinic receptor ligands.
      In an epithelial cell culture model, stimulation with nicotinic derivates (NNK and N-nitrosonornicotine) resulted in temporary (1–2.5 hours) up-regulation of ±7 subunits of the nAchR
      • Plummer III, HK
      • Dhar M
      • Schuller HM
      Expression of the alpha7 nicotinic acetylcholine receptor in human lung cells.
      and in increased proliferative activity.
      • Arredondo J
      • Chernyavsky AI
      • Grando SA
      The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells.
      The increased proliferation was reduced by nicotinic antagonists (±BTX, see later).
      • Arredondo J
      • Chernyavsky AI
      • Grando SA
      The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells.
      Stimulation with NNK showed in one study the involvement of signal transduction effectors STAT1, GATA3, and NFκB, whereas N-nitrosonornicotine activates the first two.
      • Arredondo J
      • Chernyavsky AI
      • Grando SA
      The nicotinic receptor antagonists abolish pathobiologic effects of tobacco-derived nitrosamines on BEP2D cells.
      Nicotine increases activation of AKT within minutes through.
      • West KA
      • Brognard J
      • Clark AS
      • et al.
      Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.
      Activated AKT increased phosphorylation of downstream substrates such as GSK-3, p70S6K, 4EBP-1, and FKHR.
      • West KA
      • Brognard J
      • Clark AS
      • et al.
      Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.
      This activation by nicotine was dependent on ±3- or ±4-containing nAchRs and for NNK on ±7-containing nAchRs.
      • West KA
      • Brognard J
      • Clark AS
      • et al.
      Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.
      The nicotine or NNK concentration required for AKT activation is achievable in smokers.
      • West KA
      • Brognard J
      • Clark AS
      • et al.
      Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.
      Incubation of bronchial epithelial cells with nicotine produces GM-CSF
      • Klapproth H
      • Racke K
      • Wessler I
      Acetylcholine and nicotine stimulate the release of granulocyte-macrophage colony stimulating factor from cultured human bronchial epithelial cells.
      that stimulates inflammatory cells.
      Interestingly, apoptosis is induced in nonmalignant human bronchial epithelial cells treated with damaging agents such as etoposide, ultraviolet irradiation, or hydrogen peroxide. Nicotine or NNK attenuates this apoptotic effect and results partially in a transformed phenotype manifest as loss of contact inhibition and loss of dependence on exogenous growth factors or adherence to extracellular matrix.
      • West KA
      • Brognard J
      • Clark AS
      • et al.
      Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.
      Thus, in epithelial cells, nicotine and NNK have a stimulatory effect on a growth, cell survival, and inflammation.

      CANCER

      In small cell lung cancer (SCLC) and non-SCLC (NSCLC), the same nAchR±3-±5-±7-²4 subunits as mentioned for the HBE cells are expressed.
      • West KA
      • Brognard J
      • Clark AS
      • et al.
      Rapid Akt activation by nicotine and a tobacco carcinogen modulates the phenotype of normal human airway epithelial cells.
      • Chini B
      • Clementi F
      • Hukovic N
      • Sher E
      Neuronal-type alpha-bungarotoxin receptors and the alpha 5-nicotinic receptor subunit gene are expressed in neuronal and nonneuronal human cell lines.
      • Tarroni P
      • Rubboli F
      • Chini B
      • et al.
      Neuronal-type nicotinic receptors in human neuroblastoma and small-cell lung carcinoma cell lines.
      In nonsmokers with NSCLC, a difference exists in nAchR expression, with higher expression of nAchR ±6-²3 subunit genes present in nonsmokers than in NSCLC from smokers.
      • Lam DC
      • Girard L
      • Ramirez R
      • et al.
      Expression of nicotinic acetylcholine receptor subunit genes in non-small-cell lung cancer reveals differences between smokers and nonsmokers.
      The mAchR is also expressed in most SCLC and many NSCLC.
      • Song P
      • Sekhon HS
      • Lu A
      • et al.
      M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion.
      In lung cancer cells, nicotine and NNK bind to nAchR,
      • Tsurutani J
      • Castillo SS
      • Brognard J
      • et al.
      Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells.
      whereas nicotine binds also to mAchR.
      • Carlisle DL
      • Liu X
      • Hopkins TM
      • Swick MC
      • Dhir R
      • Siegfried JM
      Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells.
      In NSCLC cell lines, nicotine leads to an increase in ±7-nAchRs.
      • Zheng Y
      • Ritzenthaler JD
      • Roman J
      • Han S
      Nicotine stimulates human lung cancer cell growth by inducing fibronectin expression.

      Loop

      Both NSCLC and SCLC cell lines synthesize and release Ach.
      • Song P
      • Sekhon HS
      • Jia Y
      • et al.
      Acetylcholine is synthesized by and acts as an autocrine growth factor for small cell lung carcinoma.
      In squamous cell carcinoma (SqCC), the enzyme choline acetyltransferase is strongly up-regulated, whereas cholinesterases are down-regulated.
      • Martinez-Moreno P
      • Nieto-Ceron S
      • Torres-Lanzas J
      • et al.
      Cholinesterase activity of human lung tumours varies according to their histological classification.
      • Song P
      • Sekhon HS
      • Fu XW
      • et al.
      Activated cholinergic signaling provides a target in squamous cell lung carcinoma.
      This combination causes prominent increase in Ach content in SqCC compared with normal lung.
      • Song P
      • Sekhon HS
      • Fu XW
      • et al.
      Activated cholinergic signaling provides a target in squamous cell lung carcinoma.
      The mechanism underlying the increased cholineacetyltransferase expression in SqCC is not clear, although nicotine itself stimulates Ach secretion.
      • Song P
      • Sekhon HS
      • Fu XW
      • et al.
      Activated cholinergic signaling provides a target in squamous cell lung carcinoma.
      In SCLC, mAchR and Ach are coexpressed.
      • Song P
      • Sekhon HS
      • Lu A
      • et al.
      M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion.
      Increased levels of Ach provide endogenous proliferative stimuli to both mAchR and nAchR. These findings suggest that an autocrine or a paracrine cholinergic pathway for mAchR and nAchR in SCLC and for nAchR in NSCLC exists see Figure 1.
      Figure thumbnail gr1
      FIGURE 1The acetyholine receptor (AchR) pathway plays a pivotal role in promotion of lung cancer. Nicotine binds with higher affinity than physiologic ligand acetylcholine (Ach) to nicotinic AchR (nAchR). Binding of ligand to nAchR results in Ca++ influx, binding of ²-arrestin and SRC. One subsequent effect is increase of Ach synthesis. Ach binds to nAchR and to muscarinic AchR (mAchR). The coexpression of Ach and AchR has been shown in SCLC and NSCLC, pointing to an autocrine or paracrine loop. Lynx1 modulates the effect of activated nAchR. nAchRs may show less desensitization from endogenous Ach and exogenous nicotine in case of decreased levels of Lynx1. Ligand binding to nAchR and mAchR lead to activated MAPK and proliferation after a few hours. Nicotine leads to increase fibronectin synthesis, which binds extracellular to ±5²1 integrin. This in turn results in increase of MAPK, leading to proliferation with a peak after 5 days. Nicotine inhibits mitochondrial apoptosis induced by chemotherapy, UV radiation, and hydrogenperoxide, thereby, prolonging cell survival. Nicotine decreases E-cadherin and ²-catenin and in combination with fibronectin it increases proinvasive effects possibly due to the loss of contact inhibition. Nicotine also leads to increase in HIF1±, with subsequent increase of VEGF stimulating neoangiogenesis. All these effects can be blocked at the level of the nAchR and the mAchR.

      Modulator of Receptor Activity

      Lynx1 is a member of a newly described family of allosteric modulators of nicotinic receptor activity. It has been shown to attenuate responses to Ach and to increase the extent to which Ach and nicotine desensitize nAchR.
      • Song P
      • Sekhon HS
      • Fu XW
      • et al.
      Activated cholinergic signaling provides a target in squamous cell lung carcinoma.
      Lynx1, the nAchR accessory protein, is expressed in normal bronchial epithelium.
      • Sekhon HS
      • Song P
      • Jia Y
      • Lindstrom J
      • Spindel ER
      Expression of lynx1 in developing lung and its modulation by prenatal nicotine exposure.
      In SqCC, Lynx1 is expressed at significantly lower levels.
      • Song P
      • Sekhon HS
      • Fu XW
      • et al.
      Activated cholinergic signaling provides a target in squamous cell lung carcinoma.
      Therefore, decreases in Lynx1 may lead to potentiate responses to exogenous nicotine and endogenous Ach.

      Proliferation

      In lung cancer, nicotine induces proliferation of tumor cells by binding to the ±7-nAchR. In this pathway, activation of SRC and Rb-Raf-1/pERK/p90RSK is involved.
      • Dasgupta P
      • Rastogi S
      • Pillai S
      • et al.
      Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways.
      • Carlisle DL
      • Liu X
      • Hopkins TM
      • Swick MC
      • Dhir R
      • Siegfried JM
      Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells.
      Stimulation with nicotine induces a Ca++ influx within seconds, which may last for 15 min.
      • Fucile S
      • Napolitano M
      • Mattei E
      Cholinergic stimulation of human microcytoma cell line H69.
      • Cattaneo MG
      • Codignola A
      • Vicentini LM
      • Clementi F
      • Sher E
      Nicotine stimulates a serotonergic autocrine loop in human small-cell lung carcinoma.
      Nicotine stimulates tumor growth in a murine model where A549 cells orthotopically grafted.
      • Carlisle DL
      • Liu X
      • Hopkins TM
      • Swick MC
      • Dhir R
      • Siegfried JM
      Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells.
      Inhibitors of nicotine at the level of ±7-nAchR (±-bungarotoxin and ±-cobratoxin) suppress this proliferative effect, suggesting that nAchRs control the rate of proliferation.
      • Carlisle DL
      • Liu X
      • Hopkins TM
      • Swick MC
      • Dhir R
      • Siegfried JM
      Nicotine activates cell-signaling pathways through muscle-type and neuronal nicotinic acetylcholine receptors in non-small cell lung cancer cells.
      • Paleari L
      • Catassi A
      • Ciarlo M
      • et al.
      Role of alpha7-nicotinic acetylcholine receptor in human non-small cell lung cancer proliferation.
      Stimulation of the mAchR in SCLC induced Ca++ release, MAPK, and AKT activation, which is associated with proliferation. Blocking experiments (antagonists and siRNA) showed that M3 subtype was responsible for Ca++ release and reduced MAPK, AKT, and inhibited proliferation.
      • Song P
      • Sekhon HS
      • Lu A
      • et al.
      M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion.
      Nicotine induces an increase in fibronectin production.
      • Zheng Y
      • Ritzenthaler JD
      • Roman J
      • Han S
      Nicotine stimulates human lung cancer cell growth by inducing fibronectin expression.
      Extracellular fibronectin binds to ±5²1 integrin, which subsequently leads to increased proliferation through ERK, PI3-K, and mTOR pathways. This indirect proliferative effect of nicotine is maximal at days 4 to 5
      • Zheng Y
      • Ritzenthaler JD
      • Roman J
      • Han S
      Nicotine stimulates human lung cancer cell growth by inducing fibronectin expression.
      and could be blocked at the level of the ±5²1 integrin receptor. These data show that nicotine has a direct short term and an indirect longer term effect on proliferation.

      Apoptosis

      Similar to the effect in HBE, nicotine diminishes apoptosis in SCLC and NSCLC cell lines.
      • Maneckjee R
      • Minna JD
      Opioids induce while nicotine suppresses apoptosis in human lung cancer cells.
      • Dasgupta P
      • Kinkade R
      • Joshi B
      • Decook C
      • Haura E
      • Chellappan S
      Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin.
      • Grozio A
      • Paleari L
      • Catassi A
      • et al.
      Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: a promising prospective in anti-cancer drug development.
      The antiapoptotic effects of nicotine were mediated by nAchR-±3 and required the AKT pathway, leading to an increased recruitment of E2F1 and concomitant dissociation of retinoblastoma tumor suppressor protein. The binding of E2F1 to the promoter of survivin and XIAP genes resulted in the up-regulation of these inhibitors of apoptosis.
      • Dasgupta P
      • Kinkade R
      • Joshi B
      • Decook C
      • Haura E
      • Chellappan S
      Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin.
      ±7-nAchR antagonists inhibited proliferation of NSCLC through mitochondria-associated apoptosis.
      • Grozio A
      • Paleari L
      • Catassi A
      • et al.
      Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: a promising prospective in anti-cancer drug development.
      Thus, nicotine has a prolonged effect on tumor cell survival by preventing apoptosis.

      Invasion

      Pathways that contribute to the proinvasive effects of nicotine include ±7-nAchR-mediated activation of Src, calcium channels, and up-regulation of EGFR. Nicotine induced down-regulation of epithelial markers, E-cadherin and ²-catenin, whereas it caused concomitant increase of mesenchymal proteins fibronectin and vimentin in A549 human NSCLC.
      • Dasgupta P
      • Rizwani W
      • Pillai S
      • et al.
      Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines.
      These effects are part of the proinvasive epithelial-mesenchymal transition phenomenon.
      Moreover, fibronectin may confer resistance to apoptosis induced by chemotherapy as has been shown in SCLC.
      • Sethi T
      • Rintoul RC
      • Moore SM
      • et al.
      Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo.
      Beside the effect on fibronectin, nicotine also stimulated HIF-1±, with subsequent increase in VEGF, stimulating angiogenesis and invasion.
      • Zhang Q
      • Tang X
      • Zhang ZF
      • Velikina R
      • Shi S
      • Le AD
      Nicotine induces hypoxia-inducible factor-1alpha expression in human lung cancer cells via nicotinic acetylcholine receptor-mediated signaling pathways.
      These data demonstrate proinvasive and angiogenic effects of nicotine.

      Survival

      In patients diagnosed with smoking-related lung cancer and who continue smoking, a negative correlation with lung cancer survival has been shown.
      • Sardari NP
      • Weyler J
      • Colpaert C
      • Vermeulen P
      • Van ME
      • Van SP
      Prognostic value of smoking status in operated non-small cell lung cancer.
      • Tammemagi CM
      • Neslund-Dudas C
      • Simoff M
      • Kvale P
      Smoking and lung cancer survival: the role of comorbidity and treatment.
      • Videtic GM
      • Stitt LW
      • Dar AR
      • et al.
      Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival.
      The reduced treatment efficacy may be well explained by the pluriform effect of nicotine on tumor cell proliferation, apoptosis, epithelial-mesenchymal transition, proinvasive, and angiogenic effects, which are reenforced by the autocrine or paracrine loop.

      Possible Treatment Options

      These effects of nicotine in lung cancer raise the question whether inhibition of ±7-nAchR activity by nontoxic agents or inhibition of its downstream mediators might open novel avenues for the therapy for cancers promoted by smoking.
      • Dasgupta P
      • Rizwani W
      • Pillai S
      • et al.
      Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines.
      Members of the type II ±-neurotoxin subfamily have high affinity for ±7-nAchR. Examples are ±-CbT and ±-bungarotoxin.
      • Grozio A
      • Paleari L
      • Catassi A
      • et al.
      Natural agents targeting the alpha7-nicotinic-receptor in NSCLC: a promising prospective in anti-cancer drug development.
      • Zhang Q
      • Tang X
      • Zhang ZF
      • Velikina R
      • Shi S
      • Le AD
      Nicotine induces hypoxia-inducible factor-1alpha expression in human lung cancer cells via nicotinic acetylcholine receptor-mediated signaling pathways.
      The latter acts as an antagonist to both ±7-nAchR and mAchR.
      Although treatment with nicotinic receptor antagonists can have significant effects on blood pressure, mAchR antagonists are better tolerated and are widely used for treatment of chronic obstructive pulmonary disease.
      • Gross NJ
      Anticholinergic agents in asthma and COPD.
      Therefore, it is not excluded that muscarinic antagonists might serve as a useful adjuvant to conventional chemotherapeutic regimens for SCLC and NSCLC, which express the autocrine cholinergic loop.
      Overall, there is no evidence that nicotine itself induces cancer, but nicotine promotes in vivo the growth of cancer cells and the proliferation of endothelial cells. This suggests that nicotine after initiation may contribute to the progression phase of cancer development. Continuation of smoking after lung cancer has been diagnosed should be discouraged because smoking may not only support tumor growth but also interferes with treatment.

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