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Sigma‐2 Receptor Agonists as Possible Antitumor Agents in Resistant Tumors: Hints for Collateral Sensitivity
Author(s) -
Niso Mauro,
Abate Carmen,
Contino Marialessandra,
Ferorelli Savina,
Azzariti Amalia,
Perrone Roberto,
Colabufo Nicola Antonio,
Berardi Francesco
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300291
Subject(s) - p glycoprotein , chemistry , receptor , doxorubicin , pharmacology , multiple drug resistance , cancer research , cell culture , tetrahydroisoquinoline , stereochemistry , biology , medicine , chemotherapy , biochemistry , genetics , antibiotics
With the aim of contributing to the development of novel antitumor agents, high‐affinity σ 2 receptor agonists were developed, with 6,7‐dimethoxy‐2‐[4‐[1‐(4‐fluorophenyl)‐1 H ‐indol‐3‐yl]butyl]‐1,2,3,4‐tetrahydroisoquinoline ( 15 ) and 9‐[4‐(6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinolin‐2‐yl)butyl]‐9 H ‐carbazole ( 25 ) showing exceptional selectivity for the σ 2 subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin‐resistant MCF7adr cell line. Surprisingly, a few compounds, including 25 , displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug‐resistant tumors. All of the compounds showed interaction with P‐glycoprotein (P‐gp), and 15 and 25 , with the greatest activity, were able to revert P‐gp‐mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ 2 receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug‐ resistant cancers.