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

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 Bunch

doi:10.1021/acs.jmedchem.7b01624

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

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 Bunch

13 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	60
Udgave nummer	23
Sider (fra-til)	9885-9904
Antal sider	20
ISSN	0022-2623
DOI	https://doi.org/10.1021/acs.jmedchem.7b01624
Status	Udgivet - 14 dec. 2017

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1021/acs.jmedchem.7b01624

Citationsformater

Gynther, M., Proietti Silvestri, I., Hansen, J. C., Hansen, K. B., Malm, T., Ishchenko, Y., Larsen, Y., Han, L., Kayser, S., Auriola, S., Petsalo, A., Nielsen, B., Pickering, D. S., & Bunch, L. (2017). 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, 60(23), 9885-9904. https://doi.org/10.1021/acs.jmedchem.7b01624

Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist. / Gynther, Mikko; Proietti Silvestri, Ilaria; Hansen, Jacob C et al.
I: Journal of Medicinal Chemistry, Bind 60, Nr. 23, 14.12.2017, s. 9885-9904.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Gynther, M, Proietti Silvestri, I, Hansen, JC, Hansen, KB, Malm, T, Ishchenko, Y, Larsen, Y, Han, L, Kayser, S, Auriola, S, Petsalo, A, Nielsen, B , Pickering, DS & Bunch, L 2017, '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, bind 60, nr. 23, s. 9885-9904. https://doi.org/10.1021/acs.jmedchem.7b01624

@article{8a429ff26a8b43b6a98e6a023bde2da9,

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

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.",

keywords = "Journal Article",

author = "Mikko Gynther and {Proietti Silvestri}, Ilaria and Hansen, {Jacob C} and Hansen, {Kasper B} and Tarja Malm and Yevheniia Ishchenko and Younes Larsen and Liwei Han and Silke Kayser and Seppo Auriola and Aleksanteri Petsalo and Birgitte Nielsen and Pickering, {Darryl S} and Lennart Bunch",

year = "2017",

month = dec,

day = "14",

doi = "10.1021/acs.jmedchem.7b01624",

language = "English",

volume = "60",

pages = "9885--9904",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "23",

}

TY - JOUR

T1 - Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist

AU - Gynther, Mikko

AU - Proietti Silvestri, Ilaria

AU - Hansen, Jacob C

AU - Hansen, Kasper B

AU - Malm, Tarja

AU - Ishchenko, Yevheniia

AU - Larsen, Younes

AU - Han, Liwei

AU - Kayser, Silke

AU - Auriola, Seppo

AU - Petsalo, Aleksanteri

AU - Nielsen, Birgitte

AU - Pickering, Darryl S

AU - Bunch, Lennart

PY - 2017/12/14

Y1 - 2017/12/14

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1021/acs.jmedchem.7b01624

DO - 10.1021/acs.jmedchem.7b01624

M3 - Journal article

C2 - 29205034

SN - 0022-2623

VL - 60

SP - 9885

EP - 9904

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -

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

Abstract

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater