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

Sigma-2 (sigma(2)) 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 sigma(2) receptor, and many sigma(2) ligands display cytotoxic actions in (resistant) cancer cells. These properties have shed light on the sigma(2) receptor as a potential druggable target to be bound/activated for the diagnosis or therapy of tumors. Additionally, diverse groups have shown how the sigma(2) 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 sigma(2) ligands in the oncology field, with a focus on MTDLs directed towards sigma(2) receptors as promising weapons against (resistant) cancer diseases.

Automated summary

The sigma(2) receptor has potential in cancer diagnosis and therapy, and MultiTarget Directed Ligands (MTDLs) show promise in overcoming pharmacokinetic issues associated with multiple drug administration.