title: Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models.
abstract: Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regulate gene expression at transcriptional and translational levels. c-KIT proto-oncogene encodes for a tyrosine kinase receptor. It is involved in several physiological processes, but it is also dysregulated in many diseases, including cancer. Two G-rich sequences able to fold into G4, have been identified in c-KIT proximal promoter, thus representing suitable targets for anticancer intervention. Herein, we screened an "in house" library of compounds for the recognition of these G4 elements and we identified three promising ligands. Their G4-binding properties were analyzed and related to their antiproliferative, transcriptional and post-transcriptional effects in MCF7 and HGC27 cell lines. Besides c-KIT, the transcriptional analysis covered a panel of oncogenes known to possess G4 in their promoters.From these studies, an anthraquinone derivative (AQ1) was found to efficiently downregulate c-KIT mRNA and protein in both cell lines. The targeted activity of AQ1 was confirmed using c-KIT-dependent cell lines that present either c-KIT mutations or promoter engineered (i.e., α155, HMC1.2 and ROSA cells).Present results indicate AQ1 as a promising compound for the target therapy of c-KIT-dependent tumors, worth of further and in depth molecular investigations.
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Zorzan
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Da Ros
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Musetti
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy.
authors.forename: Lara Zorro
authors.initials: LZ
authors.lastname: Shahidian
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy.
authors.forename: Nuno Filipe Ramos
authors.initials: NF
authors.lastname: Coelho
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Bonsembiante
authors.affiliation: Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Université Aix-Marseille (UM105), Marseille, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Létard
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy.
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Gelain
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
authors.affiliation: Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Université Aix-Marseille (UM105), Marseille, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Dubreuil
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy.
authors.forename: Mery
authors.initials: M
authors.lastname: Giantin
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.affiliation: Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Dacasto
mesh_terms: D000880:Anthraquinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D054856:G-Quadruplexes; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000880:Anthraquinones; D008024:Ligands; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019009:Proto-Oncogene Proteins c-kit
keywords: G-quadruplex; G4-ligands; anthraquinone; c-KIT; in-vitro models