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

Manuela Porru, Simona Artuso, Erica Salvati, Armandodoriano Bianco, Marco Franceschin, Maria Grazia Diodoro, Daniela Passeri, Augusto Orlandi, Francesco Savorani, Maurizio D'Incalci, Annamaria Biroccio, Carlo Leonetti

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2541-2551
Number of pages11
JournalMolecular Cancer Therapeutics
Volume14
Issue number11
DOIs
Publication statusPublished - Nov 1 2015

Fingerprint

G-Quadruplexes
Colonic Neoplasms
Telomere
EMICORON
Heterografts
Bone Marrow Cells
DNA Damage
Intestines
Neoplasms
Stomach
Theoretical Models
Lymph Nodes
Cell Proliferation
Ligands
Liver
DNA
Therapeutics
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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, Vol. 14, No. 11, 01.11.2015, p. 2541-2551.

Research output: Contribution to journalArticle

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. / Targeting G-quadruplex DNA structures by EMICORON has a strong antitumor efficacy against advanced models of human colon cancer. In: Molecular Cancer Therapeutics. 2015 ; Vol. 14, No. 11. pp. 2541-2551.
@article{6a04d37ba75c44b9b3b6b641887bc6db,
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.",
author = "Manuela Porru and Simona Artuso and Erica Salvati and Armandodoriano Bianco and Marco Franceschin and Diodoro, {Maria Grazia} and Daniela Passeri and Augusto Orlandi and Francesco Savorani and Maurizio D'Incalci and Annamaria Biroccio and Carlo Leonetti",
year = "2015",
month = "11",
day = "1",
doi = "10.1158/1535-7163.MCT-15-0253",
language = "English",
volume = "14",
pages = "2541--2551",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Targeting G-quadruplex DNA structures by EMICORON has a strong antitumor efficacy against advanced models of human colon cancer

AU - Porru, Manuela

AU - Artuso, Simona

AU - Salvati, Erica

AU - Bianco, Armandodoriano

AU - Franceschin, Marco

AU - Diodoro, Maria Grazia

AU - Passeri, Daniela

AU - Orlandi, Augusto

AU - Savorani, Francesco

AU - D'Incalci, Maurizio

AU - Biroccio, Annamaria

AU - Leonetti, Carlo

PY - 2015/11/1

Y1 - 2015/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84958168950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84958168950&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-15-0253

DO - 10.1158/1535-7163.MCT-15-0253

M3 - Article

C2 - 26304235

AN - SCOPUS:84958168950

VL - 14

SP - 2541

EP - 2551

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 11

ER -