G-quadruplex ligand-mediated CHK1 and ERα suppression in endocrine-sensitive and endocrine-resistant luminal breast cancer cells
4 affiliations
- 1Department of Science, Roma Tre University, Rome, Italy
- 2Dipartimento di Chimica, Università di Pavia, Pavia, Italy
- 3Department of Biology and Biotechnology “C.Darwin”, Sapienza University of Rome, Rome, Itlay
- 4Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
Abstract
G-quadruplex (G4)-stabilizing ligands are promising tools for inhibiting tumor cell growth in both in vitro and in vivo models. G4 stabilization interferes with DNA replication, leading to replication stress (RS) and DNA damage, and affects gene expression. Clinical development of the telomere-targeting G4 ligand RHPS4 was discontinued due to cardiotoxicity, prompting the synthesis of congeners with retained activity and improved toxicological profiles. In this study, the antiproliferative effects of RHPS4 derivatives were tested in breast cancer cell lines, MCF7, MDA-MB-231, and HCC1937, and compared with non-tumorigenic breast epithelial cells and normal fibroblasts. Among the analogues, compound 190 preferentially inhibited proliferation in MCF7 cells, an effect weakly associated with telomeric DNA damage. Similar to RHPS4, compound 190 induced RS, downregulated CHK1, and reduced ESR1 mRNA and ERα protein levels in a dose-dependent manner. Reduced transcript levels and enhanced ERα degradation support contributions from both transcriptional and post-translational mechanisms, with degradation potentially linked to RS. These effects were also confirmed in endocrine-resistant MCF7-Y537S cells. Together, these findings identify CHK1 and ERα suppression as responses to compound 190 and support further investigation of acridine-based G4 ligands in endocrine-sensitive and endocrine-resistant luminal breast cancer.
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BibTeX
@article{valenzuela2026gquadruplex,
title = {{G-quadruplex ligand-mediated CHK1 and ERα suppression in endocrine-sensitive and endocrine-resistant luminal breast cancer cells}},
author = {Martina Valenzuela and Valentina Pirota and Filippo Doria and Claudia Bellucci and Filippo Acconcia and Federico Dinoi and Erica Salvati and Francesco Berardinelli and Antonio Antoccia},
journal = {Cell Cycle},
year = {2026},
month = oct,
doi = {10.1080/15384101.2026.2753856},
url = {https://doi.org/10.1080/15384101.2026.2753856},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - G-quadruplex ligand-mediated CHK1 and ERα suppression in endocrine-sensitive and endocrine-resistant luminal breast cancer cells
AU - Martina Valenzuela
AU - Valentina Pirota
AU - Filippo Doria
AU - Claudia Bellucci
AU - Filippo Acconcia
AU - Federico Dinoi
AU - Erica Salvati
AU - Francesco Berardinelli
AU - Antonio Antoccia
PY - 2026
DA - 2026/10/30
JO - Cell Cycle
DO - 10.1080/15384101.2026.2753856
UR - https://doi.org/10.1080/15384101.2026.2753856
AB - G-quadruplex (G4)-stabilizing ligands are promising tools for inhibiting tumor cell growth in both in vitro and in vivo models. G4 stabilization interferes with DNA replication, leading to replication stress (RS) and DNA damage, and affects gene expression. Clinical development of the telomere-targeting G4 ligand RHPS4 was discontinued due to cardiotoxicity, prompting the synthesis of congeners with retained activity and improved toxicological profiles. In this study, the antiproliferative effects of RHPS4 derivatives were tested in breast cancer cell lines, MCF7, MDA-MB-231, and HCC1937, and compared with non-tumorigenic breast epithelial cells and normal fibroblasts. Among the analogues, compound 190 preferentially inhibited proliferation in MCF7 cells, an effect weakly associated with telomeric DNA damage. Similar to RHPS4, compound 190 induced RS, downregulated CHK1, and reduced ESR1 mRNA and ERα protein levels in a dose-dependent manner. Reduced transcript levels and enhanced ERα degradation support contributions from both transcriptional and post-translational mechanisms, with degradation potentially linked to RS. These effects were also confirmed in endocrine-resistant MCF7-Y537S cells. Together, these findings identify CHK1 and ERα suppression as responses to compound 190 and support further investigation of acridine-based G4 ligands in endocrine-sensitive and endocrine-resistant luminal breast cancer.
SN - 1538-4101
SN - 1551-4005
ER -