title: Selective M3 muscarinic receptor antagonist inhibits small-cell lung carcinoma growth in a mouse orthotopic xenograft model.
abstract: 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.
authors.affiliation: Department of Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Ibaraki 300-2611, Japan. Nozomi_Ami@terumo.co.jp
authors.forename: Nozomi
authors.initials: N
authors.lastname: Ami
authors.forename: Kazumi
authors.initials: K
authors.lastname: Koga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fushiki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ueno
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ogino
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ohta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020013:Calcium Signaling / Q000187:drug effects; D002217:Carbachol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D018721:Muscarinic Agonists / Q000737:chemistry / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; C448635:N-(2-(3-((1-(cyclohexylmethyl)-3-piperidinyl)methylamino)-3-oxopropyl)amino-2-oxoethyl)-3,3,3-triphenylpropionamide; D010880:Piperidines; D043587:Receptor, Muscarinic M3; D002217:Carbachol