Research Papers:

Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models

Eleonora Zorzan, Silvia Da Ros, Caterina Musetti, Lara Zorro Shahidian, Nuno Filipe Ramos Coelho, Federico Bonsembiante, Sébastien Létard, Maria Elena Gelain, Manlio Palumbo, Patrice Dubreuil, Mery Giantin, Claudia Sissi and Mauro Dacasto _

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Oncotarget. 2016; 7:21658-21675. https://doi.org/10.18632/oncotarget.7808

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Eleonora Zorzan1, Silvia Da Ros2, Caterina Musetti2, Lara Zorro Shahidian1, Nuno Filipe Ramos Coelho1, Federico Bonsembiante1, Sébastien Létard3, Maria Elena Gelain1, Manlio Palumbo2, Patrice Dubreuil3, Mery Giantin1, Claudia Sissi2, Mauro Dacasto1

1Department of Comparative Biomedicine and Food Science, University of Padua, Legnaro, Padua, Italy

2Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy

3Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Université Aix-Marseille (UM105), Marseille, France

Correspondence to:

Mauro Dacasto, e-mail: [email protected]

Claudia Sissi, e-mail: [email protected]

Keywords: c-KIT, G-quadruplex, in-vitro models, G4-ligands, anthraquinone

Received: September 14, 2015    Accepted: February 20, 2016    Published: March 01, 2016


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.

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