Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d -aspartate (NMDA) Receptor Antagonist
| Autor: | Seppo Auriola, Kasper B. Hansen, Mikko Gynther, Yevheniia Ishchenko, Darryl S. Pickering, Birgitte Nielsen, Aleksanteri Petsalo, Younes Larsen, Liwei Han, Jacob C. Hansen, Silke Kayser, Ilaria Proietti Silvestri, Tarja Malm, Lennart Bunch |
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| Rok vydání: | 2017 |
| Předmět: |
Niacinamide
0301 basic medicine Sorafenib Carcinoma Hepatocellular Antineoplastic Agents Receptors N-Methyl-D-Aspartate Article Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Drug Discovery medicine Animals Humans Cytotoxic T cell Receptor Chemistry Phenylurea Compounds Liver Neoplasms Antagonist Lipid signaling Drug Resistance Multiple 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Cancer research Molecular Medicine NMDA receptor Ionotropic glutamate receptor medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 60:9885-9904 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b01624 |
| Popis: | The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire suchwhen 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 (HCC) cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR transporters and therebyan increased accumulation of sorafenib in the cancer cells. Interference with lipid signaling pathwaysby NMDA receptor inhibition is a novel and promising strategy for reversing transporter-mediated chemoresistance in cancer cells. |
| Databáze: | OpenAIRE |
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