TY - JOUR
T1 - Role of the NMDA Receptor in the Antitumor Activity of Chiral 1,4-Dioxane Ligands in MCF-7 and SKBR3 Breast Cancer Cells
AU - Morelli, Maria Beatrice
AU - Amantini, Consuelo
AU - Nabissi, Massimo
AU - Santoni, Giorgio
AU - Wünsch, Bernhard
AU - Schepmann, Dirk
AU - Cimarelli, Cristina
AU - Pellei, Maura
AU - Santini, Carlo
AU - Fontana, Stefano
AU - Mammoli, Valerio
AU - Quaglia, Wilma
AU - Bonifazi, Alessandro
AU - Giannella, Mario
AU - Giorgioni, Gianfabio
AU - Piergentili, Alessandro
AU - Del Bello, Fabio
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/4/11
Y1 - 2019/4/11
N2 - The potent N-methyl-d-aspartate (NMDA) receptor antagonists 1-3 have been demonstrated to show antiproliferative and cytotoxic effects in MCF-7 and SKBR3 breast cancer cell lines. To improve the knowledge about the role played by the NMDA receptor in the antitumor activity of these compounds, the enantiomers of 1 were prepared and evaluated for their affinity for the phencyclidine (PCP) site of the NMDA receptor and for their cytotoxic effect in MCF-7 and SKBR3 cell lines, both expressing the NMDA receptor. The (S)-1 enantiomer, showing negligible affinity for the PCP site, exhibited antiproliferative activity higher than that of (R)-1, which instead bound the PCP site. The downregulation of NMDA GluN1 expression resulted in a decreased (S)-1-induced cytotoxicity and apoptotic cell death, unequivocally demonstrating the involvement of the NMDA receptor in the antitumor effect of this compound. Due to its interesting biological profile, (S)-1 represents a lead compound to develop novel antitumor agents for breast cancer treatment.
AB - The potent N-methyl-d-aspartate (NMDA) receptor antagonists 1-3 have been demonstrated to show antiproliferative and cytotoxic effects in MCF-7 and SKBR3 breast cancer cell lines. To improve the knowledge about the role played by the NMDA receptor in the antitumor activity of these compounds, the enantiomers of 1 were prepared and evaluated for their affinity for the phencyclidine (PCP) site of the NMDA receptor and for their cytotoxic effect in MCF-7 and SKBR3 cell lines, both expressing the NMDA receptor. The (S)-1 enantiomer, showing negligible affinity for the PCP site, exhibited antiproliferative activity higher than that of (R)-1, which instead bound the PCP site. The downregulation of NMDA GluN1 expression resulted in a decreased (S)-1-induced cytotoxicity and apoptotic cell death, unequivocally demonstrating the involvement of the NMDA receptor in the antitumor effect of this compound. Due to its interesting biological profile, (S)-1 represents a lead compound to develop novel antitumor agents for breast cancer treatment.
KW - 1,4-dioxane compounds
KW - NMDA receptor
KW - apoptosis
KW - breast cancer
KW - silencing of NMDA GluN1 subunit
UR - https://www.scopus.com/pages/publications/85064242778
UR - https://www.scopus.com/pages/publications/85064242778#tab=citedBy
U2 - 10.1021/acsmedchemlett.8b00536
DO - 10.1021/acsmedchemlett.8b00536
M3 - Article
AN - SCOPUS:85064242778
SN - 1948-5875
VL - 10
SP - 511
EP - 516
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 4
ER -