The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells

Abstract

Recent reports suggest that N-methyl-d-aspartate receptor (NMDAR) blockade by MK-801 decreases tumor growth. Thus, we investigated whether other ionotropic glutamate receptor (iGluR) antagonists were also able to modulate the proliferation of melanoma cells. On the other hand, the antiestrogen tamoxifen (TAM) decreases the proliferation of melanoma cells, and is included in combined therapies for melanoma. As the efficacy of TAM is limited by its metabolism, we investigated the effects of the NMDAR antagonist MK-801 in combination with TAM and its active metabolites, 4-hydroxytamoxifen (OHTAM) and endoxifen (EDX). The NMDAR blockers MK-801 and memantine decreased mouse melanoma K1735-M2 cell proliferation. In contrast, the NMDAR competitive antagonist APV and the AMPA and kainate receptor antagonist NBQX did not affect cell proliferation, suggesting that among the iGluR antagonists only the NMDAR channel blockers inhibit melanoma cell proliferation. The combination of antiestrogens with MK-801 potentiated their individual effects on cell biomass due to diminished cell proliferation, since it decreased the cell number and DNA synthesis without increasing cell death. Importantly, TAM metabolites combined with MK-801 promoted cell cycle arrest in G1. Therefore, the data obtained suggest that the activity of MK-801 and antiestrogens in K1735-M2 cells is greatly enhanced when used in combination.

Rethinking tamoxifen in the management of melanoma: New answers for an old question

“…In our laboratory, we have demonstrated that the key active metabolite of tamoxifen, endoxifen, has a more powerful cytostatic action in a mouse melanoma cell line than the prodrug (Ribeiro et al, 2013a(Ribeiro et al, , 2014, suggesting that the efficacy of tamoxifen in melanoma may also be limited by the individual metabolism or the simultaneous administration of medication, as described in breast cancer. Thus, future trials in melanoma patients taking tamoxifen should include therapeutic drug monitoring.…”

“…Importantly, recent work performed in our laboratory has demonstrated that both endoxifen and 4-hydroxytamoxifen are more effective than the parent drug in the reduction of the mouse melanoma cell line K1735-M2 proliferation (Ribeiro et al, 2013a(Ribeiro et al, , 2014, which is a model of aggressive melanoma (Repesh, 1989). These results raise the question whether the efficacy of tamoxifen in melanoma may also be affected by individual metabolism variability and simultaneous intake of other drugs, as demonstrated in breast cancer, and should be taken into account in future studies in melanoma patients in order to establish the better patient profile for a successful response to tamoxifen.…”

The Route to ‘Chemobrain’ - Computational probing of neuronal LTP pathway

“…Interestingly, peripheral NMDA receptors are also drug targets to evade multidrug resistance in cancer by virtue of their ability to downregulate ABC transporters 97 . Such is case of compound MK-801, which noncompetitively antagonizes NMDA receptor 98 .…”

Neuroendocrine Factors in Melanoma Pathogenesis

“…Furthermore, mouse melanoma cell proliferation was inhibited by blocking NMDA receptors with MK-801 and the effect was amplified when antiestrogens were associated; among all iGluRs, only the blocking of NMDA receptors was effective in controlling melanoma growth [ 116 ].…”