Selective M3 Muscarinic Receptor Antagonist Inhibits Small-Cell Lung Carcinoma Growth in a Mouse Orthotopic Xenograft Model
Selective M3 Muscarinic Receptor Antagonist Inhibits Small-Cell Lung Carcinoma Growth in a Mouse Orthotopic Xenograft Model
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DOI：
10.1254/jphs.10308fp
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发表时间：
2011-05-01
影响因子：
3.5
通讯作者：
Ohta, Hisashi
中科院分区：
文献类型：
--
作者：
Ami, Nozomi;Koga, Kazumi;Ohta, Hisashi
在小细胞肺癌（SCLC）中，乙酰胆碱（acetylcholine, ACh）是合成和分泌的，它通过激活其受体毒蕈碱受体（muscarinic receptor, mAChR）和烟碱受体（nictinic receptor, nAChR）作为一种自分泌生长因子。本研究研究了阻断人SCLC细胞系NCI-H82中M-3 mAChR对肿瘤生长的影响。我们使用了高选择性的M-3毒蕈碱拮抗剂N-（2-[3-（[3R]-1-（环己基甲基）-3-胡椒碱基]-甲基胺）-3-氧丙基]氨基-2-氧乙基）-3,3,3-三苯基丙酰胺（J-115311）。我们的研究结果表明，J-115311抑制了SCLC细胞中由一种毒蕈碱激动剂——卡巴醇引起的细胞内钙的增加。J-115311也能抑制SCLC细胞的体外生长。在小鼠原位异种移植模型中，当NCI-H82细胞接种于左肺上叶时，J-115311剂量依赖性地抑制肿瘤生长。这些发现表明，阻断M-3 mAChR可以抑制SCLC的肿瘤生长，提示M-3毒蕈碱拮抗剂作为抗癌药物的潜在治疗作用。
In small cell lung carcinoma (SCLC), acetylcholine (ACh) is synthesized and secreted, and it acts as an autocrine growth factor through activation of its receptors, muscarinic receptor (mAChR) and nicotinic receptor (nAChR). Alteration of tumor growth by blockade of M-3 mAChR in a human SCLC cell line, NCI-H82, was investigated in the present study. We used a highly selective M-3 muscarinic antagonist, N-(2-[3-([3R]-1-(cyclohexylmethyl)-3-piperidinyl]-methylamino)-3-oxopropyl]amino-2-oxoethyl)-3,3,3-triphenyl-propioamide (J-115311). Our results show that J-115311 inhibited the increased intracellular calcium elicited by carbachol, a muscarinic agonist, in SCLC cells. J-115311 also inhibited SCLC cell growth in vitro. In a mouse orthotopic xenograft model, J-115311 dose-dependently reduced tumor growth when NCI-H82 cells were inoculated into the upper left lobe of the lung. These findings indicate that blockade of M-3 mAChR can suppress tumor growth in SCLC, suggesting the potential therapeutic utility of M-3 muscarinic antagonists as anti-cancer agents.