Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy

William G North,1 Fuli Liu,1 Konstantin H Dragnev,1,2 Eugene Demidenko3 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA; 2Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA; 3Department of Community...

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Autores principales:	North WG, Liu F, Dragnev KH, Demidenko E
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	small-cell lung cancer NMDA receptors inhibitors combination therapy Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/6c18d3a3e95a48b581858a80bfe82022
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spelling	oai:doaj.org-article:6c18d3a3e95a48b581858a80bfe820222021-12-02T11:08:53ZSmall-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy1179-1438https://doaj.org/article/6c18d3a3e95a48b581858a80bfe820222019-01-01T00:00:00Zhttps://www.dovepress.com/small-cell-lung-cancer-growth-inhibition-synergism-between-nmda-recept-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438William G North,1 Fuli Liu,1 Konstantin H Dragnev,1,2 Eugene Demidenko3 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA; 2Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA; 3Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA Background: Small-cell lung cancer (SCLC) has a poor prognosis since there is currently no effective therapy for commonly recurring disease. In our previous study, both primary and recurrent human tumors have been shown to express functional N-methyl-D-aspartate (NMDA) receptors, and blockade of these receptors with GluN1 and GluN2B antagonists decreased tumor cell viability in vitro, and growth of tumor xenografts in nu/nu mice. Materials and methods: In this study, we examine the influence of the GluN2B antagonist ifenprodil and the channel-blocker antagonist memantine, on cell viability and growth of tumor xenografts of recurrent SCLC (rSCLC) in mice. Results: Both antagonists significantly reduced cell viability and levels of components of the ERK1/2 pathway, increased apoptosis, and at very safe levels significantly reduced the growth of tumors in mice. Each antagonist and topotecan had additive effects to reduce cell viability with significant synergy demonstrated for the case of memantine. More significantly, combination treatments of xenografts in mice with ifenprodil and the chemotherapeutic agent topotecan produced clear additive effects that completely stopped tumor growth. Moreover, the ifenprodil and topotecan combination showed excellent supra-addition or synergy of inhibition for tumors ≤300 mm in size (P=4.7E−4). Combination treatment of memantine with topotecan also showed clear addition but, unlike ifenprodil, no synergy for the doses chosen. Conclusion: Since topotecan is a drug of choice for treatment of rSCLC, our findings suggest that combining this agent with NMDA receptor blockade using the GluN2B antagonist, ifenprodil, will significantly improve patient outcomes. Keywords: small-cell lung cancer, NMDA receptors, inhibitors, combination therapyNorth WGLiu FDragnev KHDemidenko EDove Medical Pressarticlesmall-cell lung cancerNMDA receptorsinhibitorscombination therapyTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol Volume 11, Pp 15-23 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	small-cell lung cancer NMDA receptors inhibitors combination therapy Therapeutics. Pharmacology RM1-950
spellingShingle	small-cell lung cancer NMDA receptors inhibitors combination therapy Therapeutics. Pharmacology RM1-950 North WG Liu F Dragnev KH Demidenko E Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy
description	William G North,1 Fuli Liu,1 Konstantin H Dragnev,1,2 Eugene Demidenko3 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA; 2Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA; 3Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, USA Background: Small-cell lung cancer (SCLC) has a poor prognosis since there is currently no effective therapy for commonly recurring disease. In our previous study, both primary and recurrent human tumors have been shown to express functional N-methyl-D-aspartate (NMDA) receptors, and blockade of these receptors with GluN1 and GluN2B antagonists decreased tumor cell viability in vitro, and growth of tumor xenografts in nu/nu mice. Materials and methods: In this study, we examine the influence of the GluN2B antagonist ifenprodil and the channel-blocker antagonist memantine, on cell viability and growth of tumor xenografts of recurrent SCLC (rSCLC) in mice. Results: Both antagonists significantly reduced cell viability and levels of components of the ERK1/2 pathway, increased apoptosis, and at very safe levels significantly reduced the growth of tumors in mice. Each antagonist and topotecan had additive effects to reduce cell viability with significant synergy demonstrated for the case of memantine. More significantly, combination treatments of xenografts in mice with ifenprodil and the chemotherapeutic agent topotecan produced clear additive effects that completely stopped tumor growth. Moreover, the ifenprodil and topotecan combination showed excellent supra-addition or synergy of inhibition for tumors ≤300 mm in size (P=4.7E−4). Combination treatment of memantine with topotecan also showed clear addition but, unlike ifenprodil, no synergy for the doses chosen. Conclusion: Since topotecan is a drug of choice for treatment of rSCLC, our findings suggest that combining this agent with NMDA receptor blockade using the GluN2B antagonist, ifenprodil, will significantly improve patient outcomes. Keywords: small-cell lung cancer, NMDA receptors, inhibitors, combination therapy
format	article
author	North WG Liu F Dragnev KH Demidenko E
author_facet	North WG Liu F Dragnev KH Demidenko E
author_sort	North WG
title	Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy
title_short	Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy
title_full	Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy
title_fullStr	Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy
title_full_unstemmed	Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy
title_sort	small-cell lung cancer growth inhibition: synergism between nmda receptor blockade and chemotherapy
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/6c18d3a3e95a48b581858a80bfe82022
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Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy

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