title: Targeting G-Quadruplex DNA Structures by EMICORON Has a Strong Antitumor Efficacy against Advanced Models of Human Colon Cancer.
abstract: We previously identified EMICORON as a novel G-quadruplex (G4) ligand showing high selectivity for G4 structures over the duplex DNA, causing telomere damage and inhibition of cell proliferation in transformed and tumor cells. Here, we evaluated the antitumoral effect of EMICORON on advanced models of human colon cancer that could adequately predict human clinical outcomes. Our results showed that EMICORON was well tolerated in mice, as no adverse effects were reported, and a low ratio of sensitivity across human and mouse bone marrow cells was observed, indicating a good potential for reaching similar blood levels in humans. Moreover, EMICORON showed a marked therapeutic efficacy, as it inhibited the growth of patient-derived xenografts (PDX) and orthotopic colon cancer and strongly reduced the dissemination of tumor cells to lymph nodes, intestine, stomach, and liver. Finally, activation of DNA damage and impairment of proliferation and angiogenesis are proved to be key determinants of EMICORON antitumoral activity. Altogether, our results, performed on advanced experimental models of human colon cancer that bridge the translational gap between preclinical and clinical studies, demonstrated that EMICORON had an unprecedented antitumor activity warranting further studies of EMICORON-based combination treatments.
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors: Manuela
authors: M
authors: Porru
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors: Simona
authors: S
authors: Artuso
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy.
authors: Erica
authors: E
authors: Salvati
authors: Department of Chemistry, University of Rome "Sapienza", Rome, Italy.
authors: Armandodoriano
authors: A
authors: Bianco
authors: Department of Chemistry, University of Rome "Sapienza", Rome, Italy.
authors: Marco
authors: M
authors: Franceschin
authors: Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy.
authors: Maria Grazia
authors: MG
authors: Diodoro
authors: Department of Biopathology and Image Diagnostics, Anatomic Pathology Institute, University of Rome "Tor Vergata", Rome, Italy.
authors: Daniela
authors: D
authors: Passeri
authors: Department of Biopathology and Image Diagnostics, Anatomic Pathology Institute, University of Rome "Tor Vergata", Rome, Italy.
authors: Augusto
authors: A
authors: Orlandi
authors: Department of Food Science, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
authors: Francesco
authors: F
authors: Savorani
authors: Department of Oncology, Pharmacological Research Institute "Mario Negri", Milan, Italy.
authors: Maurizio
authors: M
authors: D'Incalci
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy. leonetti@ifo.it biroccio@ifo.it.
authors: Annamaria
authors: A
authors: Biroccio
authors: Experimental Chemotherapy Laboratory, Regina Elena National Cancer Institute, Rome, Italy. leonetti@ifo.it biroccio@ifo.it.
authors: Carlo
authors: C
authors: Leonetti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054856:G-Quadruplexes / Q000187:drug effects*; D006801:Humans; D007094:Imides / Q000494:pharmacology*; D008297:Male; D055432:Metabolomics / Q000379:methods; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009690:Nucleic Acid Conformation / Q000187:drug effects*; D010880:Piperidines / Q000494:pharmacology*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C000610391:EMICORON; D007094:Imides; D010880:Piperidines