RESUMO
Adenocarcinoma and glioblastoma cell lines express α7- and α9α10-containing nicotinic acetylcholine receptors (nAChRs), whose activation promotes tumor cell growth. On these cells, the triethylammoniumethyl ether of 4-stilbenol MG624, a known selective antagonist of α7 and α9α10 nAChRs, has antiproliferative activity. The structural analogy of MG624 with the mitocan RDM-4'BTPI, triphenylphosphoniumbutyl ether of pterostilbene, suggested us that molecular hybridization among their three substructures (stilbenoxy residue, alkylene linker, and terminal onium) and elongation of the alkylene linker might result in novel antitumor agents with higher potency and selectivity. We found that lengthening the ethylene bridge in the triethylammonium derivatives results in more potent and selective toxicity toward adenocarcinoma and glioblastoma cells, which was paralleled by increased α7 and α9α10 nAChR antagonism and improved ability of reducing mitochondrial ATP production. Elongation of the alkylene linker was advantageous also for the triphenylphosphonium derivatives resulting in a generalized enhancement of antitumor activity, associated with increased mitotoxicity.
Assuntos
Glioblastoma/patologia , Espécies Reativas de Oxigênio/química , Receptores Nicotínicos/metabolismo , Estilbenos/química , Estilbenos/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , HumanosRESUMO
BACKGROUND AND PURPOSE: Tobacco smoke contains many classes of carcinogens and although nicotine is unable to initiate tumourigenesis in humans and rodents, it promotes tumour growth and metastasis in lung tumours by acting on neuronal nicotinic ACh receptors (nAChRs). The aim of this study was to identify molecularly, biochemically and pharmacologically which nAChR subtypes are expressed and functionally activated by nicotine in lung cancer cell lines. EXPERIMENTAL APPROACH: We used A549 and H1975 adenocarcinoma cell lines derived from lung tumours to test the in vitro effects of nicotine, and nAChR subtype-specific peptides and compounds. KEY RESULTS: The two adenocarcinoma cell lines express distinctive nAChR subtypes, and this affects their nicotine-induced proliferation. In A549 cells, nAChRs containing the α7 or α9 subunits not only regulate nicotine-induced cell proliferation but also the activation of the Akt and ERK pathways. Blocking these nAChRs by means of subtype-specific peptides, or silencing their expression by means of subunit-specific siRNAs, abolishes nicotine-induced proliferation and signalling. Moreover, we found that the α7 antagonist MG624 also acts on α9-α10 nAChRs, blocks the effects of nicotine on A549 cells and has dose-dependent cytotoxic activity. CONCLUSIONS AND IMPLICATIONS: These results highlight the pathophysiological role of α7- and α9-containing receptors in promoting non-small cell lung carcinoma cell growth and intracellular signalling and provide a framework for the development of new drugs that specifically target the receptors expressed in lung tumours. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.
Assuntos
Adenocarcinoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nicotina/farmacologia , Receptores Nicotínicos/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/antagonistas & inibidores , Células A549 , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Compostos de Amônio Quaternário/farmacologia , Estilbenos/farmacologia , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7/metabolismoRESUMO
Each of the four aromatic -CH= of (S,R)-2-pyrrolidinyl-1,4-benzodioxane [(S,R)-6] and of its epimer at the dioxane stereocenter (S,S)-6, previously reported as α4ß2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at α4ß2, α3ß4 and α7 nAChR subtypes and compared to their common carbaisostere. It turned out that such isosteric substitutions are highly detrimental, but with the important exception of the S,R stereoisomer of the pyrrolidinyl-pyridodioxane with the pyridine nitrogen adjacent to the dioxane and seven atoms distant from the pyrrolidine nitrogen. Indeed, this stereo/regioisomer not only maintained the α4ß2 affinity of [(S,R)-6], but also greatly improved in selectivity over the α3ß4 and α7 subtypes and, most importantly, exhibited a highly selective α4ß2 partial agonism. The finding that [(S,R)-6] is, instead, an unselective α4ß2 antagonist indicates that the benzodioxane substructure confers affinity for the α4ß2 nAChR binding site, but activation of this receptor subtype needs benzodioxane functionalization under strict steric requirements, such as the previously reported 7-OH substitution or the present isosteric modification.
Assuntos
Dioxanos/química , Dioxanos/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Receptores Nicotínicos/metabolismo , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Desenho de Fármacos , Células HEK293 , Humanos , Relação Estrutura-AtividadeRESUMO
Lung cancer is the leading cause of cancer-related deaths worldwide. Smoking accounts for approximately 70% of the cases of non- small cell lung cancer (NSCLC) and 90% of the cases of small-cell lung cancer (SCLC), although some patients develop lung cancer without a history of smoking. Nicotine is the most active addictive component of tobacco smoke. It does not initiate tumorigenesis in humans and rodents, but it alters the pathophysiology of lung cells by inducing the secretion of growth factors, neurotransmitters and cytokines, and promotes tumour growth and metastases by inducing cell cycle progression, migration, invasion, angiogenesis and the evasion of apoptosis. Most of these effects are a result of nicotine binding and activation of cell-surface neuronal nicotinic acetylcholine receptors (nAChRs) and downstream intracellular signalling cascades, and many are blocked by nAChR subtype-selective antagonists. Recent genome-wide association studies have revealed single nucleotide polymorphisms of nAChR subunits that influence nicotine dependence and lung cancer. This review describes the molecular basis of nAChR structural and functional diversity in normal and cancer lung cells, and the genetic alterations facilitating smoking-induced lung cancers. It also summarises current knowledge concerning the intracellular pathways activated by nicotine and other compounds present in tobacco smoke.
Assuntos
Antineoplásicos/farmacologia , Agonistas Colinérgicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Receptores Nicotínicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Polimorfismo de Nucleotídeo Único/genética , Receptores Nicotínicos/genéticaRESUMO
Some unichiral analogues of 2R,2'S-2-(1'-methyl-2'-pyrrolidinyl)-7-hydroxy-1,4-benzodioxane, a potent and selective α4ß2-nAChR partial agonist, were designed by opening dioxane and replacing hydroxyl carbon with nitrogen. The resulting 3-pyridyl and m-hydroxyphenyl ethers have high α4ß2 affinity and good subtype selectivity, which get lost if OH is removed from phenyl or the position of pyridine nitrogen is changed. High α4ß2 affinity and selectivity are also attained by meta hydroxylating the 3-pyridyl and the phenyl ethers of (S)-N-methylprolinol and the phenyl ether of (S)-2-azetidinemethanol, known α4ß2 agonists, although the interaction mode of the aryloxymethylene substructure cannot be assimilated to that of benzodioxane. Indeed, the α4ß2 and α3ß4 functional tests well differentiate behaviors that the binding tests homologize: both the 3-hydroxyphenyl and the 5-hydroxy-3-pyridyl ether of N-methylprolinol are α4ß2 full agonists, but only the latter is highly α4ß2/α3ß4 selective, while potent and selective partial α4ß2 agonism characterizes the hydroxybenzodioxane derivative and its two opened semirigid analogues.