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Repurposing FDA-approved drugs to target G-quadruplexes in breast cancer
Federica Moraca1, Valentina Arciuolo1, Simona Marzano1
1Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
Abstract:
Breast cancer, a leading cause of cancer-related mortality in women, is characterized by genomic instability and aberrant gene expression, often influenced by noncanonical nucleic acid structures such as G-quadruplexes (G4s). These structures, commonly found in the promoter regions and 5'-untranslated RNA sequences of several oncogenes, play crucial roles in regulating transcription and translation. Stabilizing these G4 structures offers a promising therapeutic strategy for targeting key oncogenic pathways. In this study, we employed a drug repurposing approach to identify FDA-approved drugs capable of binding and stabilizing G4s in breast cancer-related genes. Using ligand-based virtual screening and biophysical methods, we identified several promising compounds, such as azelastine, belotecan, and irinotecan, as effective G4 binders, with significant antiproliferative effects in breast cancer cell lines. Notably, belotecan and irinotecan exhibited a synergistic mechanism, combining G4 stabilization with their established topoisomerase I inhibition activity to enhance cytotoxicity in cancer cells. Our findings support the therapeutic potential of G4 stabilization in breast cancer, validate drug repurposing as an efficient strategy to identify G4-targeting drugs, and highlight how combining G4 stabilization with other established drug activities may improve anticancer efficacy.
Insights
Researchers identified FDA-approved drugs, like belotecan and irinotecan, that stabilize G-quadruplexes (G4s) in breast cancer genes. This strategy enhances cancer cell killing by combining G4 stabilization with existing drug mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer is a major cause of death in women, linked to genomic instability and altered gene expression.
- Noncanonical nucleic acid structures, like G-quadruplexes (G4s), in oncogene regulatory regions influence gene expression.
- Stabilizing G4 structures presents a therapeutic avenue for breast cancer treatment.
Purpose of the Study:
- To identify FDA-approved drugs that bind and stabilize G-quadruplexes (G4s) in breast cancer-related genes using drug repurposing.
- To evaluate the antiproliferative effects of identified G4-stabilizing compounds in breast cancer cell lines.
Main Methods:
- Ligand-based virtual screening was employed to identify potential G4-binding drugs.
- Biophysical methods were used to confirm G4 binding and stabilization.
- Antiproliferative activity was assessed in breast cancer cell lines.
Main Results:
- Azelastine, belotecan, and irinotecan were identified as effective G4 binders with antiproliferative effects.
- Belotecan and irinotecan demonstrated a synergistic effect by combining G4 stabilization with topoisomerase I inhibition.
- This combination significantly enhanced cytotoxicity in cancer cells.
Conclusions:
- G-quadruplex stabilization holds therapeutic promise for breast cancer.
- Drug repurposing is an effective strategy for discovering G4-targeting agents.
- Combining G4 stabilization with other drug activities may improve anticancer efficacy.
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