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 (CRC) 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 (PDXs)and orthotopic CRC, and strongly reduced the dissemination of tumor cells to lymphnodes, intestine, stomach and liver. Finally, activation of DNA damage, 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 CRC 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.

Targeting G-quadruplex DNA structures by EMICORON has a strong antitumor efficacy against advanced models of human colon cancer / Porru, Manuela; Artuso, Simona; Salvati, Erica; Bianco, Armandodoriano; Franceschin, Marco; Diodoro, Maria Grazia; Passeri, Daniela; Orlandi, Augusto; Savorani, Francesco; D'Incalci, Maurizio; Biroccio, Annamaria; Leonetti, Carlo. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - STAMPA. - 14:11(2015), pp. 2541-2551. [10.1158/1535-7163.MCT-15-0253]

Targeting G-quadruplex DNA structures by EMICORON has a strong antitumor efficacy against advanced models of human colon cancer

BIANCO, Armandodoriano;FRANCESCHIN, MARCO;
2015

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 (CRC) 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 (PDXs)and orthotopic CRC, and strongly reduced the dissemination of tumor cells to lymphnodes, intestine, stomach and liver. Finally, activation of DNA damage, 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 CRC 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.
2015
G-quadruplexes; telomere; human telomeric
01 Pubblicazione su rivista::01a Articolo in rivista
Targeting G-quadruplex DNA structures by EMICORON has a strong antitumor efficacy against advanced models of human colon cancer / Porru, Manuela; Artuso, Simona; Salvati, Erica; Bianco, Armandodoriano; Franceschin, Marco; Diodoro, Maria Grazia; Passeri, Daniela; Orlandi, Augusto; Savorani, Francesco; D'Incalci, Maurizio; Biroccio, Annamaria; Leonetti, Carlo. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - STAMPA. - 14:11(2015), pp. 2541-2551. [10.1158/1535-7163.MCT-15-0253]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/799376
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