Sigma‐2 Receptor Agonists as Possible Antitumor Agents in Resistant Tumors: Hints for Collateral Sensitivity

Abstract

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.

Elements in support of the ‘non-identity’ of the PGRMC1 protein with the σ2 receptor

“…3) which were previously reported to exert σ 2 mediated antiproliferative action. Among these compounds, siramesine and PB28 are two reference σ 2 agonists whose antiproliferative σ 2 mediated effect has been shown in diverse tumor cell lines as well as in vivo tumor models (Zeng et al, 2012;Hornick et al, 2012Hornick et al, , 2010Niso et al, 2013;Abate et al, 2011Abate et al, , 2012bBerardi et al, 2009). Six concentrations of the compounds were used (from 1 μM to 100 μM) to investigate their antiproliferative action in MCF7, MCF7_SH and MCF7_PGRMC1 cell lines (Fig.…”

Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

“…More systematic characterization of ATP levels and metabolic fuel utilization in drug-resistant cells is clearly warranted. A number of compounds have been demonstrated to elicit collateral sensitivity and include Tiopronin (Goldsborough et al, 2011), Desmosdumotin (Nakagawa-Goto et al, 2008), NSC73306 , Dp44mT (Whitnall et al, 2006), and sigma-2 receptor agonists (Niso et al, 2013). These compounds impart collateral sensitivity; however, their mechanism remains unclear to date.…”

From mixed sigma-2 receptor/P-glycoprotein targeting agents to selective P-glycoprotein modulators: Small structural changes address the mechanism of interaction at the efflux pump

“…With the aim of targeting s 2 receptors, many classes of s 2 ligands were developed and several high affinity s 2 receptor ligands were found to interact with P-gp, either as P-gp substrates or inhibitors [10e13]. A few s 2 receptor agonists were found to be endowed with Collateral Sensitivity (CS): their antiproliferative activity was more potent in P-gp-overexpressing cells than in P-gpnegative cells [11,13]. Further investigation led to link the CS property of these s 2 agonists to their potent interaction as substrates at the P-gp and the consequent depletion of ATP to support P-gp-mediated active efflux of these substrates.…”