Article open access publication

Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist.

Journal of Medicinal Chemistry, American Chemical Society (ACS), ISSN 0022-2623

Volume 60, 23, 2017

DOI:10.1021/acs.jmedchem.7b01624, Dimensions: pub.1095857252, PMC: PMC5788303, PMID: 29205034,



  1. (1) University of Eastern Finland, grid.9668.1
  2. (2) University of Copenhagen, grid.5254.6, KU
  3. (3) University of Montana, grid.253613.0


The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire such when treated with anticancer drugs. In this work, we describe the discovery of a peripherally restricted, potent, competitive NMDA receptor antagonist 1l by a structure-activity study of the broad-acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR transporters and thereby an increased accumulation of sorafenib in the cancer cells. Interference with lipid signaling pathways by NMDA receptor inhibition is a novel and promising strategy for reversing transporter-mediated chemoresistance in cancer cells.


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University of Copenhagen

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2017: Blocked

Research area: Medicine

Danish Bibliometrics Indicator

2017: Level 2

Research area: Medicine

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Times Cited: 8

Field Citation Ratio (FCR): 2.74

Relative Citation ratio (RCR): 0.82

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Green, Accepted