Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 9885-9904 |
| Number of pages | 20 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 60 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 14 2017 |
Funding
We would like to thank the Lundbeck Foundation and the Danish Medical Research Council for financial support of the medicinal chemistry work reported herein. Emil Aaltonen Foundation and The Finnish Cultural Foundation are acknowledged for the funding regarding the pharmacokinetic analysis, transporter expression modulation, and cytotoxicity studies. Finally, the National Institutes of Health (P20GM103546 and R01NS097536) is acknowledged for financial support in regards to the functional characterization of 1l at NMDA receptors. Mrs. Sari Ukkonen is acknowledged for technical assistance. The murine hcc cells were a kind donation by Prof. Lars Zender, Tübingen University.
| Funder number |
|---|
| R01NS097536 |
| P20GM103546 |
