Persico Carolina, Iaccarino Nunzia, Romano Francesca, Giustiniano Mariateresa, Russo Camilla, Laneri Sonia, Di Lorenzo Ritamaria, Aiello Immacolata, Abate Sara, Izzo Luana, Merlino Francesco, Brancaccio Diego, Pagano Bruno, Amato Jussara, Marzano Simona, D'Aria Federica, De Tito Stefano, Di Porzio Anna, Randazzo Antonio
Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
The Molecular Cell Biology of Autophagy, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
NAR Cancer. 2024 Oct 30;6(4):zcae042. doi: 10.1093/narcan/zcae042. eCollection 2024 Dec.
The use of chemotherapeutics has achieved considerable success in cancer therapy; however, their toxicity can severely impact patients' health. In this study, aiming to reduce the doses and potential side effects of traditional chemotherapeutics, we systematically treated A375MM human melanoma cells with seven clinically approved antineoplastic drugs, in combination with three well-characterized G-quadruplex (G4) ligands, using either simultaneous or sequential dosing schedules. Interestingly, the G4 binders synergized with most of the investigated anticancer drugs, with the degree of synergism being strictly dependent on both the treatment schedule and the drug sequence employed. Notably, some of the synergistic combinations showed selective toxicity toward melanoma cells over nontumorigenic human keratinocytes. Furthermore, immunofluorescence experiments highlighted the potential implication of G4 structures in the molecular mechanisms driving the synergistic interaction between some chemotherapeutics and G4 binders. Overall, our systematic study supports the combination of G4-interacting molecules with standard antineoplastic drugs as a promising antitumor strategy.
化疗药物在癌症治疗中取得了显著成功；然而，它们的毒性会严重影响患者健康。在本研究中，为了降低传统化疗药物的剂量和潜在副作用，我们使用同步或序贯给药方案，用七种临床批准的抗肿瘤药物与三种特性明确的G-四链体（G4）配体系统地处理A375MM人黑色素瘤细胞。有趣的是，G4结合剂与大多数研究的抗癌药物产生协同作用，协同程度严格取决于治疗方案和所用药物顺序。值得注意的是，一些协同组合对黑色素瘤细胞显示出比对非致瘤性人角质形成细胞的选择性毒性。此外，免疫荧光实验突出了G4结构在驱动某些化疗药物与G4结合剂之间协同相互作用的分子机制中的潜在作用。总体而言，我们的系统研究支持将与G4相互作用的分子与标准抗肿瘤药物联合使用作为一种有前景的抗肿瘤策略。
