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Sigma Receptor (?R) Ligands with Antiproliferative and Anticancer Activity.

ABSTRACT: Sigma receptor (?R) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various ?R ligands generate cancer cell death in vitro and in vivo. These ?R ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy.

SUBMITTER: Georgiadis MO

PROVIDER: S-EPMC6151391 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity.

Georgiadis Markos-Orestis MO Karoutzou Olga O Foscolos Angeliki-Sofia AS Papanastasiou Ioannis I

Molecules (Basel, Switzerland) 20170825 9

Sigma receptor (σR) ligands have proven to be useful as cancer diagnostics and anticancer therapeutics and their ligands have been developed as molecular probes in oncology. Moreover, various σR ligands generate cancer cell death in vitro and in vivo. These σR ligands have exhibited promising results against numerous human and rodent cancers and are investigated under preclinical and clinical study trials, indicating a new category of drugs in cancer therapy. ...[more]

PMID: 28841173

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Project description:Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

Project description:The sigma 1 receptor (?1R) and the mu-opioid receptor (MOR) regulate the transient receptor potential (TRP) V1 calcium channel. A series of proteins are involved in the cross-regulation between MORs and calcium channels like the glutamate N-methyl-D-aspartate receptor (NMDAR), including the histidine triad nucleotide-binding protein 1 (HINT1), calmodulin (CaM), and the ?1R. Thus, we assessed whether similar mechanisms also apply to the neural TRP ankyrin member 1 (TRPA1), TRP vanilloid member 1 (TRPV1), and TRP melastatin member 8 (TRPM8). Our results indicate that ?1R and CaM bound directly to cytosolic regions of these TRPs, and this binding increased in the presence of calcium. By contrast, the association of HINT1 with these TRPs was moderately dependent on calcium. The ?1R always competed with CaM for binding to the TRPs, except for its binding to the TRPA1 C-terminal where ?1R binding cooperated with that of CaM. However, ?1R dampened HINT1 binding to the TRPA1 N-terminal. When the effect of ?1R ligands was addressed, the ?1R agonists PRE084 and pregnenolone sulfate enhanced the association of the ?1R with the TRPM8 N-terminal and TRPV1 C-terminal in the presence of physiological calcium, as seen for the ?1R-NMDAR interactions. However, these agonists dampened ?1R binding to the TRPA1 and TRPV1 N-terminal domains, and also to the TRPA1 C-terminal, as seen for ?1R-binding immunoglobulin protein (BiP) interactions in the endoplasmic reticulum (ER). By contrast, the ?1R antagonists progesterone and S1RA reduced the association of ?1R with TRPA1 and TRPV1 C-terminal regions, as seen for the ?1R-NMDAR interactions. Conversely, they enhanced the ?1R interaction with the TRPA1 N-terminal, as seen for ?1R-BiP interactions, whereas they barely affected the association of ?1R with the TRPV1 N-terminal. Thus, depending on the calcium channel and the cytosolic region examined, the ?1R agonists pregnenolone sulfate and PRE084 opposed or collaborated with the ?1R antagonists progesterone and S1RA to disrupt or promote such interactions. Through the use of cloned cytosolic regions of selected TRP calcium channels, we were able to demonstrate that ?1R ligands exhibit biased activity to regulate particular ?1R interactions with other proteins. Since ?1Rs are implicated in essential physiological processes, exploiting such ligand biases may represent a means to develop more selective and efficacious pharmacological interventions.

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Sigma Receptor (?R) Ligands with Antiproliferative and Anticancer Activity.

Publications

Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity.

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