Antibacterial fluoroquinolones have emerged as potential anticancer drugs, thus prompting the synthesis of novel molecules with improved cytotoxic characteristics. Ciprofloxacin and norfloxacin derivatives, previously synthesized by our group, showed higher anticancer potency than their progenitors. However, no information about their mechanisms of action was reported. In this study, we selected the most active among these promising molecules and evaluated, on a panel of breast (including those triple-negative) and bladder cancer cell lines, their ability to induce cell cycle alterations and apoptotic and necrotic cell death through cytofluorimetric studies. Furthermore, inhibitory effects on cellular migration, metalloproteinase, and/or acetylated histone protein levels were also evaluated by the scratch/wound healing assay and Western blot analyses, respectively. Finally, the DNA relaxation assay was performed to confirm topoisomerase inhibition. Our results indicate that the highest potency previously observed for the derivatives could be related to their ability to induce G2/M cell cycle arrest and apoptotic and/or necrotic cell death. Moreover, they inhibited cellular migration, probably by reducing metalloproteinase levels and histone deacetylases. Finally, topoisomerase inhibition, previously observed in silico, was confirmed. In conclusion, structural modifications of progenitor fluoroquinolones resulted in potent anticancer derivatives possessing multiple mechanisms of action, potentially exploitable for the treatment of aggressive/resistant cancers.
抗菌氟喹诺酮类药物已成为潜在的抗癌药物，这促使人们合成具有更强细胞毒性特征的新型分子。本课题组先前合成的环丙沙星和诺氟沙星衍生物显示出比其母体化合物更高的抗癌效力，但其作用机制尚未明确。本研究选取了这些候选分子中活性最高的化合物，通过细胞流式分析技术，在一组乳腺癌（包括三阴性乳腺癌）和膀胱癌细胞系中评估了其诱导细胞周期改变、凋亡及坏死性细胞死亡的能力。此外，分别通过划痕/伤口愈合实验和蛋白质印迹分析评估了其对细胞迁移、基质金属蛋白酶及乙酰化组蛋白水平的抑制作用。最后通过DNA松弛实验验证了拓扑异构酶抑制活性。研究结果表明，先前观察到的衍生物高效力可能与其诱导G2/M期细胞周期阻滞、凋亡及/或坏死性细胞死亡的能力相关。此外，这些衍生物可能通过降低基质金属蛋白酶水平和抑制组蛋白去乙酰化酶活性来抑制细胞迁移。最终证实了先前计算机模拟预测的拓扑异构酶抑制作用。综上所述，通过对母体氟喹诺酮类药物的结构修饰，获得了具有多重作用机制的高效抗癌衍生物，这些机制在侵袭性/耐药性癌症治疗中具有潜在应用价值。
肿瘤(癌症)患者之家