jm7b01624_si_001.csv (1.11 kB)
Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N‑Methyl‑d‑aspartate (NMDA) Receptor Antagonist
dataset
posted on 2017-12-04, 21:49 authored by Mikko Gynther, Ilaria Proietti Silvestri, Jacob C. Hansen, Kasper B. Hansen, Tarja Malm, Yevheniia Ishchenko, Younes Larsen, Liwei Han, Silke Kayser, Seppo Auriola, Aleksanteri Petsalo, Birgitte Nielsen, Darryl S. Pickering, Lennart BunchThe
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.