Targeting neuronal nicotinic receptors in cancer: new ligands and potential side-effects.
Targeting neuronal nicotinic receptors in cancer: new ligands and potential side-effects.
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靶向癌症中的神经元烟碱受体：新配体和潜在副作用。
DOI：
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发表时间：
2012
影响因子：
2.8
通讯作者：
A. Becchetti
中科院分区：
文献类型：
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作者：
P. Ambrosi;A. Becchetti
在神经系统中，神经元烟碱乙酰胆碱受体（nAChRs）介导快速兴奋性突触后电位以及ACh的较慢旁分泌作用。它们也在非神经组织中广泛表达，包括肿瘤组织，这很有趣，因为吸烟是癌症的一个既定风险因素。此外，最近的证据将编码α3/α5/β4 nAChR亚基的基因簇归因于肺癌和尼古丁成瘾的发展中的作用。尼古丁和烟草衍生的致癌N-亚硝胺的许多细胞效应可能是由nAChR激活引起的，其调节细胞增殖、迁移、凋亡和新血管生成。尽管如此，nAChR在肿瘤中的确切作用很难确定，因为癌细胞表达各种各样的烟碱亚基，其功能尚不清楚。选择性靶向nAChRs亚型的专利化合物越来越多，有望更好地了解这些通道在特定细胞类型中的生理学，并提出新的诊断和治疗方法。然而，在目前的状态下，这些化合物的彻底的功能研究仍然有限，它们是否作为激动剂，拮抗剂或部分激动剂往往是不清楚的。激活剂和抑制剂之间如此模糊的区别使得表达系统的详细研究对于生理学理解和概述可能的副作用都是非常必要的。
In the nervous system, the neuronal nicotinic acetylcholine receptors (nAChRs) mediate fast excitatory postsynaptic potentials as well as slower paracrine actions of ACh. They are also widely expressed in non-nervous tissue, including the neoplastic, which is intriguing as smoking is an established risk factor for cancer. Moreover, recent evidence attributes to the gene cluster coding for the α3/α5/β4 nAChR subunits a role in both development of lung cancer and nicotine addiction. Many cellular effects of nicotine and the tobacco-derived carcinogenic N-nitrosamines are probably caused by nAChR activation, which regulates cell proliferation, migration, apoptosis and neoangiogenesis. Nonetheless, the precise nAChR roles in tumors are difficult to determine because cancer cells express a wide variety of nicotinic subunits, whose function is unclear. Patented compounds which selectively target nAChRs subtypes are increasingly available and will hopefully allow better understanding of the physiology of these channels in specific cell types, as well as suggest novel diagnostic and therapeutic approaches. At the present state, however, thorough functional studies of these compounds are still limited and whether they act as agonists, antagonists or partial agonists is often unclear. Such a blurred distinction between activators and inhibitors makes detailed studies in expression systems sorely needed for both physiological understanding and outlining the possible side-effects.