Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

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Abstract

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.

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Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2.

A. Aliprantis, R. Yang, M R Mark … (1999)

Apoptosis is implicated in the generation and resolution of inflammation in response to bacterial pathogens. All bacterial pathogens produce lipoproteins (BLPs), which trigger the innate immune response. BLPs were found to induce apoptosis in THP-1 monocytic cells through human Toll-like receptor-2 (hTLR2). BLPs also initiated apoptosis in an epithelial cell line transfected with hTLR2. In addition, BLPs stimulated nuclear factor-kappaB, a transcriptional activator of multiple host defense genes, and activated the respiratory burst through hTLR2. Thus, hTLR2 is a molecular link between microbial products, apoptosis, and host defense mechanisms.

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Purification, molecular cloning, and expression of the mammalian sigma1-binding site.

E Kempner, A Flandorfer, H Glossmann … (1996)

Sigma-ligands comprise several chemically unrelated drugs such as haloperidol, pentazocine, and ditolylguanidine, which bind to a family of low molecular mass proteins in the endoplasmic reticulum. These so-called sigma-receptors are believed to mediate various pharmacological effects of sigma-ligands by as yet unknown mechanisms. Based on their opposite enantioselectivity for benzomorphans and different molecular masses, two subtypes are differentiated. We purified the sigma1-binding site as a single 30-kDa protein from guinea pig liver employing the benzomorphan(+)[3H]pentazocine and the arylazide (-)[3H]azidopamil as specific probes. The purified (+)[3H]pentazocine-binding protein retained its high affinity for haloperidol, pentazocine, and ditolylguanidine. Partial amino acid sequence obtained after trypsinolysis revealed no homology to known proteins. Radiation inactivation of the pentazocine-labeled sigma1-binding site yielded a molecular mass of 24 +/- 2 kDa. The corresponding cDNA was cloned using degenerate oligonucleotides and cDNA library screening. Its open reading frame encoded a 25.3-kDa protein with at least one putative transmembrane segment. The protein expressed in yeast cells transformed with the cDNA showed the pharmacological characteristics of the brain and liver sigma1-binding site. The deduced amino acid sequence was structurally unrelated to known mammalian proteins but it shared homology with fungal proteins involved in sterol synthesis. Northern blots showed high densities of the sigma1-binding site mRNA in sterol-producing tissues. This is also in agreement with the known ability of sigma1-binding sites to interact with steroids, such as progesterone.

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The pharmacology of sigma-1 receptors.

Tangui Maurice, Tsung-Ping Su (2009)

Originally considered an enigmatic protein, the sigma-1 receptor has recently been identified as a unique ligand-regulated molecular chaperone in the endoplasmic reticulum of cells. This discovery causes us to look back at the many proposed roles of this receptor, even before its molecular function was identified, in many diseases such as methamphetamine or cocaine addiction, amnesia, pain, depression, Alzheimer's disease, stroke, retinal neuroprotection, HIV infection, and cancer. In this review, we examine the reports that have clearly shown an agonist-antagonist relationship regarding sigma-1 receptors in models of those diseases and also review the relatively known mechanisms of action of sigma-1 receptors in an attempt to spur the speculation of readers on how the sigma-1 receptor at the endoplasmic reticulum might relate to so many diseases. We found that the most prominent action of sigma-1 receptors in biological systems including cell lines, primary cultures, and animals is the regulation and modulation of voltage-regulated and ligand-gated ion channels, including Ca(2+)-, K(+)-, Na(+), Cl(-), and SK channels, and NMDA and IP3 receptors. We found that the final output of the action of sigma-1 receptor agonists is to inhibit all above-mentioned voltage-gated ion channels, while they potentiate ligand-gated channels. The inhibition or potentiation induced by agonists is blocked by sigma-1 receptor antagonists. Other mechanisms of action of sigma-1 receptors, and to some extent those of sigma-2 receptors, were also considered. We conclude that the sigma-1 and sigma-2 receptors represent potential fruitful targets for therapeutic developments in combating many human diseases.

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Journal

Journal ID (nlm-ta): Molecules

Journal ID (iso-abbrev): Molecules

Journal ID (publisher-id): molecules

Title: Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry

Publisher: MDPI

ISSN (Electronic): 1420-3049

Publication date (Electronic): 25 August 2017

Publication date Collection: September 2017

Volume: 22

Issue: 9

Electronic Location Identifier: 1408

Affiliations

School of Health Sciences, Department of Pharmacy, Division of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 15784 Athens, Greece; aopf_9@ 123456hotmail.com (M.-O.G.); olgakarou@ 123456gmail.com (O.K.); angelique.lumiere@ 123456windowslive.com (A.-S.F.)

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[* ]Correspondence: papanastasiou@ 123456pharm.uoa.gr ; Tel.: +30-210-727-4828

Author information

Markos-Orestis Georgiadis https://orcid.org/0000-0002-9804-9675

Olga Karoutzou https://orcid.org/0000-0002-2516-5253

Angeliki-Sofia Foscolos https://orcid.org/0000-0001-8123-5060

Ioannis Papanastasiou https://orcid.org/0000-0001-6974-2561

Article

Publisher ID: molecules-22-01408

DOI: 10.3390/molecules22091408

PMC ID: 6151391

PubMed ID: 28841173

SO-VID: ba005d25-1f27-46f9-91f9-fa091a394a32

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Sigma Receptor (σR) Ligands with Antiproliferative and Anticancer Activity

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Most cited references 132

Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2.

Purification, molecular cloning, and expression of the mammalian sigma1-binding site.

The pharmacology of sigma-1 receptors.

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