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

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.

New Pharmacological Strategies against Pancreatic Adenocarcinoma: The Multifunctional Thiosemicarbazone FA4

“…FA4 was obtained according to a polypharmacology strategy, following other σ2 receptor-targeting thiosemicarbazones (e.g., MLP44 and PS3 ) that had shown promising antitumor properties in a panel of immortalized human PDAC cells and in a murine (KP02) tumor model [ 17 , 18 ]. All these thiosemicarbazones were designed with the aim to bind σ-2 receptors, that are overexpressed in a number of cancers [ 19 , 20 ], and chelate metals (in particular iron and copper ions) in order to obtain synergic effects by adding the effects of the alteration of the redox state of cells due to metal chelation to the cytotoxic properties proper of the σ2 agonists [ 21 ].…”

“…Following a multi-targeting drug synthesis approach, we designed a series of σ2 receptor agonists [ 21 ]. A preliminary screening on different commercial PDAC cell lines, indicated FA4 , based on the modification of the structure of σ2 reference agonist siramesine, as the lead compound in terms of cytotoxicity [ 10 ].…”

Screening of σ2 Receptor Ligands and In Vivo Evaluation of 11C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ2 Receptor Brain PET Tracer

“…To investigate the specificity of [ 11 C]-(±)- 7 for the σ 2 receptor, PET studies were performed with several blocking agents (1 mg/kg iv, 10 min prior to radiotracer administration): haloperidol ( K i for σ 1 = 1.5 nM, and K i for σ 2 = 24.2 nM) for σ 1 receptor binding, siramesine ( K i for σ 1 = 12.6 nM, and K i for σ 2 = 10.5 nM) for σ 2 receptor binding, and (±)- 7 for nonspecific binding (Figure A). TACs of each group were obtained (Figure B).…”

Retinal Photoreceptor Protection in an AMD-Related Mouse Model by Selective Sigma-1 or Sigma-2 Receptor Modulation

“…Furthermore, using an in vitro model [ 42 ] ( Figure S1 ), we found that pretreatment of ARPE19 cells with CM398 or (+)-pentazocine was protective for cell survival against paraquat-induced cytotoxicity, whereas PB28, which targets both S1R and S2R [ 43 ] did not show a protective effect. This result is consistent with the in vivo evidence that CM398 inhibits retinal autofluorescence ( Figure 2 ), which is thought to be mainly emitted by the cytotoxic wastes accumulated in the RPE [ 40 , 44 ].…”