σ2 Receptor and Its Role in Cancer with Focus on a MultiTarget Directed Ligand (MTDL) Approach.

Francesca Serena Abatematteo,Enza Lacivita,Carmen Abate,Mauro Niso

doi:10.3390/molecules26123743

Francesca Serena Abatematteo, Enza Lacivita + Show 2 more

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https://doi.org/10.3390/molecules26123743

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Abstract

Sigma-2 (σ2) is an endoplasmic receptor identified as the Endoplasmic Reticulum (ER) transmembrane protein TMEM97. Despite its controversial identity, which was only recently solved, this protein has gained scientific interest because of its role in the proliferative status of cells; many tumor cells from different organs overexpress the σ2 receptor, and many σ2 ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the σ2 receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the σ2 receptor can be exploited for the targeted delivery of the anticancer drugs to tumors. As the cancer disease is a multifactorial pathology with multiple cell populations, a polypharmacological approach is very often needed. Instead of the simultaneous administration of different classes of drugs, the use of one molecule that interacts with diverse pharmacological targets, namely MultiTarget Directed Ligand (MTDL), is a promising and currently pursued strategy, that may overcome the pharmacokinetic problems associated with the administration of multiple molecules. This review aims to point out the progress regarding the σ2 ligands in the oncology field, with a focus on MTDLs directed towards σ2 receptors as promising weapons against (resistant) cancer diseases.

Highlights

Treatment of cancer, which is a major public health problem worldwide and the second leading cause of death [1], has changed a great deal over the years
We only briefly discussed about the σ receptor, while we focused more on the σ subtype and the structural insights of the σ-directed MTLDs in the context of cancer
Another step in this direction was taken by Riganas and co-workers, who dev (1-adamantyl)diarylalkylamines in which the adamantyl moiety was introduced w aim to produce activity at Na+ channels, whose involvement in cancer has been [29,30]

Summary

Introduction

Treatment of cancer, which is a major public health problem worldwide and the second leading cause of death (in the USA) [1], has changed a great deal over the years. Piperazine derivative 1 (Figure 3) exerted the best cytotoxic effect on ovarian cancer cells (IGROV-1) and a good in vitro antiangiogenic activity on normal cell lines such as the Human Umbilical Vein Endothelial Cells (HUVEC) Another step in this direction was taken by Riganas and co-workers, who dev (1-adamantyl)diarylalkylamines in which the adamantyl moiety was introduced w aim to produce activity at Na+ channels, whose involvement in cancer has been [29,30]. The hypothesis was validated by radioligand binding experiments performed on overexpressing and knockdown PGRMC1 cell lines [37] On this basis, subsequent studies treated the σ2 receptor and PGRMC1 as the same entity despite some inconsistencies, and pharmacological tools useful to detect PGRMC1 mediated activity were used to define the pharmacological action of σ2 receptor ligands.

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Conclusions