title: Genomic action of permanently charged tamoxifen derivatives via estrogen receptor-alpha.
abstract: Tamoxifen is a selective estrogen receptor modulator widely used in oncology and reproductive endocrinology. In order to decrease its non-desirable effects and elucidate mechanisms of action, permanently charged tamoxifen derivatives (PCTDs) have been reported. Whether PCTDs have genomic effects remains controversial. Since the clinical relevance of tamoxifen, the necessity to have new anticancer drugs, and in order to gain insights into the mechanisms of action of PCTDs, we obtained six quaternary ammonium salts derived from tamoxifen including three new compounds. We characterized them by nuclear magnetic resonance, X-ray diffraction, electron microscopy, and/or high performance liquid chromatography, and detected them in cell lysates by liquid chromatography coupled to mass spectrometry. We evaluated their binding to estrogen receptor-alpha (ERalpha, their effect on the transcriptional activity mediated by ERalpha (gene reporter assays), and the proliferation of cancer cells (MCF-7 and cells from a cervical cancer primary culture). Structural studies demonstrated the expected identity of the molecules. All PCTDs did bind to ERalpha, one of them induced ERalpha-mediated transcription while two others inhibited such genomic action. Accordingly, PCTDs were detected in cell lysates. PCTDs inhibited cell proliferation, noteworthy, two of them displayed higher inhibition than tamoxifen. Structure-activity analysis suggests that PCTDs permanent positive charge and the length of the aliphatic chain might be associated to the biological responses studied. We suggest genomic effects as a mechanism of action of PCTDs. The experimental approaches here used could lead to a better design of new therapeutic molecules and help to elucidate molecular mechanisms of new anticancer drugs.
authors.affiliation: Department of Pharmacology, Centro de Investigación y de Estudios Avanzados, Avenida Instituto Politécnico Nacional 2508, México DF 07360, Mexico. jueshalom@gmail.com
authors.forename: Claudia
authors.initials: C
authors.lastname: Rivera-Guevara
authors.forename: Víctor
authors.initials: V
authors.lastname: Pérez-Alvarez
authors.forename: Rocío
authors.initials: R
authors.lastname: García-Becerra
authors.forename: David
authors.initials: D
authors.lastname: Ordaz-Rosado
authors.forename: Martha Sonia
authors.initials: MS
authors.lastname: Morales-Ríos
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hernández-Gallegos
authors.forename: Austin J
authors.initials: AJ
authors.lastname: Cooney
authors.forename: María Elena
authors.initials: ME
authors.lastname: Bravo-Gómez
authors.forename: Fernando
authors.initials: F
authors.lastname: Larrea
authors.forename: Javier
authors.initials: J
authors.lastname: Camacho
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013629:Tamoxifen / Q000737:chemistry* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D013629:Tamoxifen