The combination of glutamate receptor antagonist MK-801 with tamoxifen and its active metabolites potentiates their antiproliferative activity in mouse melanoma K1735-M2 cells.
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.
Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
Mariana P C
MP
Ribeiro
Center for Neuroscience and Cell Biology, Flow Cytometry Unit, University of Coimbra, 3000-354 Coimbra, Portugal.
Isabel
I
Nunes-Correia
Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. Electronic address: aesantos@ci.uc.pt.
Armanda E
AE
Santos
Center for Neuroscience and Cell Biology, University of Coimbra, 3000-354 Coimbra, Portugal; Laboratory of Biochemistry, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
José B A
JB
Custódio
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D018691:Excitatory Amino Acid Antagonists; D013629:Tamoxifen; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen; D016291:Dizocilpine Maleate
Antiestrogens; Cell proliferation; Glutamate receptor antagonists; Melanoma