Sigma-2 receptor agonists as possible antitumor agents in resistant tumors: Hints for collateral sensitivity

Mauro Niso, Carmen Abate, Marialessandra Contino, Savina Ferorelli, Amalia Azzariti, Roberto Perrone, Nicola Antonio Colabufo, Francesco Berardi

Research output: Contribution to journalArticlepeer-review


With the aim of contributing to the development of novel antitumor agents, high-affinity σ2 receptor agonists were developed, with 6,7-dimethoxy-2-[4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl]-1,2,3, 4-tetrahydroisoquinoline (15) and 9-[4-(6,7-dimethoxy-1,2,3,4- tetrahydroisoquinolin-2-yl)butyl]-9H-carbazole (25) showing exceptional selectivity for the σ2 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 σ2 receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug- resistant cancers. Collateral damage: We developed promising σ2 ligands for alternative strategies against multidrug-resistant cancer. New high-affinity σ2 agonists display antiproliferative activity in breast tumor cells; their interaction with P-gp generates higher activity in resistant than in parent cells (collateral sensitivity). Compounds co-administered with doxorubicin revert P-gp-mediated resistance.

Original languageEnglish
Pages (from-to)2026-2035
Number of pages10
Issue number12
Publication statusPublished - Dec 2013


  • antitumor agents
  • breast cancer
  • collateral sensitivity
  • multidrug resistance
  • sigma receptors

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine


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