title: Perylene and coronene derivatives binding to G-rich promoter oncogene sequences efficiently reduce their expression in cancer cells.
abstract: A novel approach to cancer therapeutics is emerging in the field of G-quadruplex (G4) ligands, small molecules designed to stabilize four-stranded structures that can form at telomeres as well as in other genomic sequences, including oncogene promoter sequences, 5'-UTR regions and introns. In this study, we investigated the binding activity of perylene and coronene derivatives PPL3C, CORON and EMICORON to G4 structures formed within the promoter regions of two important cancer-related genes, c-MYC and BCL-2, and their biochemical effects on gene and protein expression. In order to fully characterize the ability of the selected ligands to bind and stabilize the G4 structures originated by the c-MYC and BCL-2 promoter sequences, we performed electrospray ionization mass spectrometry (ESI-MS), Fluorescence Resonance Energy Transfer (FRET) measurements, Circular Dichroism (CD) spectra and polymerase stop assay. Altogether our results showed that the ligands had a high capacity in binding and stabilizing the G4 structures within the c-MYC and BCL-2 promoter sequences in vitro. Notably, when we evaluated by quantitative real-time PCR and western blotting analysis, the effects of treatment with the different G4 ligands on c-MYC and BCL2 expression in a human melanoma cell line, EMICORON appeared the most effective compound in reducing the mRNA and protein levels of both genes. These results encourage to consider EMICORON as a promising example of multimodal class of an antineoplastic drug, affecting different tumor crucial pathways simultaneously: telomere maintenance (as previously described), cell proliferation and apoptosis via down-regulation of both c-MYC and BCL-2 (this paper).
authors.affiliation: Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Department of Biology and Biotechnology 'Charles Darwin', University of Rome "Sapienza", 00185 Rome, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Micheli
authors.affiliation: Department of Chemistry, University of Rome "Sapienza", 00185 Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Altieri
authors.affiliation: Department of Chemistry, University of Rome "Sapienza", 00185 Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cianni
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cingolani
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Iachettini
authors.affiliation: Department of Chemistry, University of Rome "Sapienza", 00185 Rome, Italy.
authors.forename: Armandodoriano
authors.initials: A
authors.lastname: Bianco
authors.affiliation: Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Leonetti
authors.affiliation: Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Department of Biology and Biotechnology 'Charles Darwin', University of Rome "Sapienza", 00185 Rome, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cacchione
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Biroccio
authors.affiliation: Department of Chemistry, University of Rome "Sapienza", 00185 Rome, Italy. Electronic address: marco.franceschin@uniroma1.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Franceschin
authors.affiliation: Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, 00144 Rome, Italy. Electronic address: angela.rizzo@ifo.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
mesh_terms: D045744:Cell Line, Tumor; D020862:GC Rich Sequence; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes; D010569:Perylene / Q000493:pharmacokinetics / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics
chemical_list: C000595707:BCL2 protein, human; C489427:MYC protein, human; D011083:Polycyclic Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D010569:Perylene; C012256:coronene
keywords: Binding affinity; G-quadruplex; Oncogene promoters