Sigma-2 Receptor: Past, Present and Perspectives on Multiple Therapeutic Exploitations

Abate, Carmen; Niso, Mauro; Berardi, Francesco

doi:10.4155/fmc-2018-0072

Cited by 37 publications

(39 citation statements)

References 93 publications

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“…Abate and colleagues have employed a variety of approaches to generate these compounds and have produced fluorescent S2R ligands, nanoparticles that can be used as tools in S2R research, and multi-target agents intended to have cytotoxic effects (Abate, Niso and Berardi, 2018;Abate et al, 2019). To accomplish these goals, the lead compounds were decorated, in the appropriate position, with alkyl linkers bridging the pharmacophore from either a fluorescent tag or a fluorescent nanoparticle as the quantum dot (Abate et al, 2011(Abate et al, , 2014Niso et al, 2015;Pati et al, 2017).…”

Section: Development Of S2r Ligandsmentioning

confidence: 99%

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Izzo

Colom‐Cadena

Riad

et al. 2020

eNeuro

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The sigma-2 receptor (S2R) complex has been implicated in central nervous system disorders ranging from anxiety and depression to neurodegenerative disorders such as Alzheimer's disease (AD). The proteins comprising the S2R complex impact processes including autophagy, cholesterol synthesis, progesterone signaling, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. While there has been much progress in understanding the role of S2R in cellular processes and its potential therapeutic value, a great deal remains unknown. The International Symposium on Sigma-2 Receptors is held in conjunction with the annual Society for Neuroscience conference in order to promote collaboration and advance the field of S2R research. This review summarizes updates presented at the Fourth International Symposium on Sigma-2 Receptors: Role in Health and Disease, a Satellite Symposium held at the 2019 Society for Neuroscience (SfN) conference. Interdisciplinary members of the S2R research community presented both previously published and preliminary results from ongoing studies of the role of S2R in cellular metabolism, the anatomical and cellular expression patterns of S2R, the relationship between S2R and amyloid beta in AD, the role of S2R complex protein PGRMC1 in health and disease, and the efforts to design new S2R ligands for the purposes of research and drug development. The proceedings from this symposium are reported here as an update on the field of S2R research, as well as to highlight the value of the symposia that occur yearly in conjunction with the SfN conference.

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Section: Development Of S2r Ligandsmentioning

confidence: 99%

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Izzo

Colom‐Cadena

Riad

et al. 2020

eNeuro

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“…Sigma-2 receptors, lately identified as TMEM97 proteins, are overexpressed in diverse types of cancers and their modulation leads to cell death upon the activation of a number of still investigated pathways [35][36][37][38][39][40][41][42][43][44][45]. Several sigma-2 receptor high-affinity ligands have been developed during recent decades (and lately reviewed), revealing cytotoxic activity through pathways that appear to be molecule-dependent and cell-type-dependent, with mechanisms that span from caspase-dependent apoptosis, autophagy, increase in ROS, and mithocondrial superoxide production [36,37,40,44]. Some sigma-2 ligands were surprisingly found to be able to kill doxorubicin-resistant cells more than the non-resistant counterparts (breast cancer cells MCF7/DX over MCF7 cells, non-small cell lung cancer A549/DX over A549 cells, colon cancer HT29/DX over HT29 cells) [28,29,33].…”

Section: Introductionmentioning

confidence: 99%

“…Three compounds, derived from three different classes of sigma-2 receptor ligands ( Figure 1: [41]; and F400 6,7-dime thoxy-2-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propionyl]-1,2,3,4 tetrahydroisoquinoline) [42] emerged as MRP1 modulators in the preliminary screening and for this reason they were further evaluated in the appropriate MDR cell line models and in a preclinical in vivo model. affinity ligands have been developed during recent decades (and lately reviewed), revealing cytotoxic activity through pathways that appear to be molecule-dependent and cell-type-dependent, with mechanisms that span from caspase-dependent apoptosis, autophagy, increase in ROS, and mithocondrial superoxide production [36,37,40,44]. Some sigma-2 ligands were surprisingly found to be able to kill doxorubicin-resistant cells more than the non-resistant counterparts (breast cancer cells MCF7/DX over MCF7 cells, non-small cell lung cancer A549/DX over A549 cells, colon cancer HT29/DX over HT29 cells) [28,29,33].…”

Section: Introductionmentioning

confidence: 99%

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

Riganti

Giampietro

Kopecka

et al. 2020

IJMS

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Multidrug resistance (MDR) is the main obstacle to current chemotherapy and it is mainly due to the overexpression of some efflux transporters such as MRP1. One of the most studied strategies to overcome MDR has been the inhibition of MDR pumps through small molecules, but its translation into the clinic unfortunately failed. Recently, a phenomenon called collateral sensitivity (CS) emerged as a new strategy to hamper MDR acting as a synthetic lethality, where the genetic changes developed upon the acquisition of resistance towards a specific agent are followed by the development of hypersensitivity towards a second agent. Among our library of sigma ligands acting as MDR modulators, we identified three compounds, F397, F400, and F421, acting as CS-promoting agents. We deepened their CS mechanisms in the “pure” model of MRP1-expressing cells (MDCK-MRP1) and in MRP1-expressing/drug resistant non-small cell lung cancer cells (A549/DX). The in vitro results demonstrated that (i) the three ligands are highly cytotoxic for MRP1-expressing cells; (ii) their effect is MRP1-mediated; (iii) they increase the cytotoxicity induced by cis-Pt, the therapeutic agent commonly used in the treatment of lung tumors; and (iv) their effect is ROS-mediated. Moreover, a preclinical in vivo study performed in lung tumor xenografts confirms the in vitro findings, making the three CS-promoting agents candidates for a novel therapeutic approach in lung resistant tumors.

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“…[ 3 H](+) − pentazocine exhibits a high a nity for σ1R, whereas [ 3 H]DTG binds with equal a nity to both σ1R and σ2R. Subsequent studies have revealed that these proteins are also involved in intracellular ion regulation and neuron survival [1,4,[6][7][8].…”

Section: Introductionmentioning

confidence: 99%

The Sigma 2 Receptor Promotes and the Sigma 1 Receptor Inhibits Mu-Opioid Receptor-Mediated Antinociception

Sánchez‐Blázquez

Cortés-Montero

Rodríguez-Muñoz

et al. 2020

Preprint

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The Sigma-1 receptor (σ1R) has emerged as an interesting pharmacological target because it inhibits analgesia mediated by mu-opioid receptors (MOR) and is also implicated in the development of neuropathic pain. Based on these findings, the recent cloning of the Sigma-2 receptor (σ2R) led us to investigate its potential role as a regulator of opioid analgesia and of pain hypersensitivity in σ2R knockout mice. σ2R-/- animals developed mechanical allodynia following establishment of chronic constriction injury-induced neuropathic pain, which was alleviated by the σ1R antagonist S1RA. The analgesic effects of morphine, [D-Ala, N-MePhe, Gly-ol]-encephalin (DAMGO) and β-endorphin increased in σ1R-/- mice and diminished in σ2R-/- mice. The analgesic effect of morphine was increased in σ2R-/- mice by treatment with S1RA. However, σ2R-/- mice and wild-type mice exhibited comparable antinociceptive responses to the delta receptor agonist [D-Pen2,5]-encephalin (DPDPE), the cannabinoid type 1 receptor agonist WIN55212-2 and the alfa2-adrenergic receptor agonist clonidine. These findings suggest that σ2R and σ1R have selective regulatory effects on MOR-mediated analgesia, with σ2R promoting MOR-mediated analgesia and σ1R inhibiting it. Our study may help identify new pharmacological targets for diminishing pain perception and improving opioid detoxification therapies.

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Sigma-2 Receptor: Past, Present and Perspectives on Multiple Therapeutic Exploitations

Cited by 37 publications

References 93 publications

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

The Sigma 2 Receptor Promotes and the Sigma 1 Receptor Inhibits Mu-Opioid Receptor-Mediated Antinociception

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