Moraca Federica, Arciuolo Valentina, Marzano Simona, Napolitano Fabiana, Castellano Giuliano, D'Aria Federica, Di Porzio Anna, Landolfi Laura, Catalanotti Bruno, Randazzo Antonio, Pagano Bruno, Malfitano Anna Maria, Amato Jussara
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
Department of Translational Medical Sciences, University of Naples Federico II, 80131 Naples, Italy.
Eur J Med Chem. 2025 Mar 5;285:117245. doi: 10.1016/j.ejmech.2025.117245. Epub 2025 Jan 4.
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.
乳腺癌是女性癌症相关死亡的主要原因，其特征是基因组不稳定和基因表达异常，这通常受非经典核酸结构如G-四链体（G4s）的影响。这些结构常见于几种致癌基因的启动子区域和5'-非翻译RNA序列中，在调节转录和翻译方面发挥着关键作用。稳定这些G4结构为靶向关键致癌途径提供了一种有前景的治疗策略。在本研究中，我们采用药物重新利用方法来鉴定能够结合并稳定乳腺癌相关基因中G4s的FDA批准药物。通过基于配体的虚拟筛选和生物物理方法，我们鉴定出几种有前景的化合物，如氮卓斯汀、倍洛特坎和伊立替康，它们是有效的G4结合剂，在乳腺癌细胞系中具有显著的抗增殖作用。值得注意的是，倍洛特坎和伊立替康表现出一种协同机制，将G4稳定作用与其已确立的拓扑异构酶I抑制活性相结合，以增强癌细胞中的细胞毒性。我们的研究结果支持G4稳定作用在乳腺癌中的治疗潜力，验证了药物重新利用作为鉴定G4靶向药物的有效策略，并强调了将G4稳定作用与其他已确立的药物活性相结合如何可能提高抗癌疗效。
