Small-cell lung cancer growth inhibition: synergism between NMDA receptor blockade and chemotherapy
Authors North WG, Liu F, Dragnev KH, Demidenko E
Received 14 August 2018
Accepted for publication 5 December 2018
Published 23 January 2019 Volume 2019:11 Pages 15—23
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 2
Editor who approved publication: Professor Arthur Frankel
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
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