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 Citations (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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	60
Issue number	23
Pages (from-to)	9885-9904
Number of pages	20
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.7b01624
Publication status	Published - 14 Dec 2017

Keywords

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.7b01624

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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.
In: Journal of Medicinal Chemistry, Vol. 60, No. 23, 14.12.2017, p. 9885-9904.

Research output: Contribution to journal › Journal article › Research › 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, vol. 60, no. 23, pp. 9885-9904. https://doi.org/10.1021/acs.jmedchem.7b01624

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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.",

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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

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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

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ER -

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

Abstract

Keywords

UN SDGs

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