Structural similitudes between cytotoxic antiestrogen-binding site (AEBS) ligands and cytotoxic sigma receptor ligands. evidence for a relationship between cytotoxicity and affinity for AEBS or sigma-2 receptor but not for sigma-1 receptor
Abstract
1-Benzyl-4-(N-2-pyrrolidinylethoxy)benzene (PBPE) is a cytotoxic derivative of the antitumoral drug tamoxifen. PBPE binds with high-affinity and specificity to the microsomal antiestrogen-binding site (AEBS). PBPE, as well as some other high-affinity AEBS ligands, shares structural features with high-affinity and selective sigma receptor ligands in the N-(arylethyl)-N-alkyl-2-(1-pyrrolidinyl)ethylamine class, such as BD1008, which are cytotoxic against tumoral cells. Based on these structural and pharmacological similitudes, we set out to examine whether AEBS and sigma receptors could be related binding sites. We showed that BD1008 had a high affinity for AEBS. However, prototypical sigma receptor ligands were very low-affinity competitors on AEBS. Surprisingly, AEBS ligands displayed a high affinity for sigma-1 and sigma-2 receptor subtypes, showing that AEBS and sigma receptor-binding sites were not mutually exchangeable. Moreover, phenytoin, which is an allosteric modulator of sigma-1 receptor, was a competitive inhibitor of [3H]tamoxifen on AEBS. These results suggest that the tamoxifen-binding site on AEBS and the sigma ligand-binding site on sigma receptors were not identical but related entities. We also showed here that the high-affinity and specific AEBS ligands also bound sigma receptors with high affinity. Moreover, the compounds that were capable of displacing tamoxifen from AEBS were cytotoxic against tumoral cells but not against the AEBS-deficient cell line Rtx-6. These results confirm that AEBS and sigma receptors might belong to the same family of proteins, and that the tamoxifen-binding site might be involved in the cytotoxicity of AEBS ligands and some classes of sigma compounds.
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TAM binds sigma 1 and 2 receptors on the endoplasmic reticulum.
“Furthermore, TAM binds other endogenous molecules, including sigma 1 and 2 receptors on the endoplasmic reticulum [10], and cholesterol epoxide hydrolase (ChEH) – an enzyme complex involved in cholesterol biosynthesis [11].”
From Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis (2015) · cites this paper as [10]
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- Authors
- Kedjouar, B., Daunes, S., Vilner, B. J., Bowen, W. D., Klaebe, A., Faye, J.-C., & Poirot, M.
- Affiliations
- Inserm (FR)
- National Institutes of Health (US)
- Corresponding author
- Poirot, Marc
- ORCID
- Poirot, Marc
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 1999-12
- Volume
- 58
- Issue
- 12
- Pages
- 1927-1939
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W1971011001
- Cited by
- 27
- References
- 42
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 2 · 2013: 1 · 2012: 1
- FWCI
- 0.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pharmacological Receptor Mechanisms and Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- antiestrogen binding sites, sigma-2 receptor, sigma-1 receptor, tamoxifen, cytotoxicity, receptor binding sites, phenytoin, allosteric modulation, structure-activity relationship, microsomal proteins
- MeSH terms
- Sigma-1 Receptor, Allosteric Regulation, Animals, Benzhydryl Compounds, Binding Sites, Cell Division, Cell Line, Humans, Ligands, Male, Phenytoin, Radioligand Assay, Structure-Activity Relationship, Tamoxifen, Tumor Cells, Cultured, Rats, Sprague-Dawley, Receptors, sigma, Antineoplastic Agents, Hormonal, Rats
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